RET

Summary

RET (ret proto-oncogene, HGNC:9967) is a protein-coding gene on chromosome 10q11.21, encoding Proto-oncogene tyrosine-protein kinase receptor Ret (P07949). Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN, ARTN, PSPN and GDF15). In precision oncology, RET Mutation confers sensitivity to Selpercatinib in Medullary Thyroid Carcinoma (CIViC Level A); 28 further curated variant–drug associations are listed below. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis.

Source: NCBI Gene 5979 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple endocrine neoplasia type 2B (Definitive, ClinGen) — +9 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 4,413 total — 104 pathogenic, 68 likely-pathogenic (top 1% of genes corpus-wide)
• GTEx eGene: eQTL in 31 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 143
• Drug target: yes — 14 curated mechanism-of-action drugs; 135 molecules with ChEMBL bioactivity (top 1% of genes corpus-wide)
• Approved drugs (ChEMBL mechanism of action): 8 — Alectinib Hydrochloride, Pralsetinib, Quizartinib, +5 more
• Precision-oncology evidence (CIViC): 29 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 6 cancer types (inferred from mutation patterns)
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.24 (highly constrained)
• MANE Select transcript: NM_020975
• Interaction hub: 3,420 STRING partners (top 2% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9967
Approved symbol	RET
Name	ret proto-oncogene
Location	10q11.21
Locus type	gene with protein product
Status	Approved
Aliases	PTC, CDHF12, RET51, CDHR16
Ensembl gene	ENSG00000165731
Ensembl biotype	protein_coding
OMIM	164761
Entrez	5979

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 4 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000355710

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 3: 1, TSL 5: 4

ENST00000355710, ENST00000340058, ENST00000498820, ENST00000615310, ENST00000638465, ENST00000640619, ENST00000671844, ENST00000672389, ENST00000683007, ENST00000683278, ENST00000683872, ENST00000684216, ENST00000713926, ENST00000935252, ENST00000935253, ENST00000935254, ENST00000935255, ENST00001014189, ENST00001079597, ENST00001079598, ENST00001139758

RefSeq mRNA: 41 — MANE Select: NM_020975 NM_001355216, NM_001406743, NM_001406744, NM_001406759, NM_001406760, NM_001406761, NM_001406762, NM_001406763, NM_001406764, NM_001406765, NM_001406766, NM_001406767, NM_001406768, NM_001406769, NM_001406770, NM_001406771, NM_001406772, NM_001406773, NM_001406774, NM_001406775, NM_001406776, NM_001406777, NM_001406778, NM_001406779, NM_001406780, NM_001406781, NM_001406782, NM_001406783, NM_001406784, NM_001406785, NM_001406786, NM_001406787, NM_001406788, NM_001406789, NM_001406790, NM_001406791, NM_001406792, NM_001406793, NM_001406794, NM_020630, NM_020975

CCDS: CCDS53525, CCDS7200

Canonical transcript exons

ENST00000355710 — 20 exons

Exon	Start	End
ENSE00001095904	43109031	43109230
ENSE00001095907	43106376	43106571
ENSE00001095923	43102342	43102629
ENSE00001095944	43116584	43116731
ENSE00001095946	43104952	43105193
ENSE00001164770	43118373	43118480
ENSE00001164787	43114480	43114736
ENSE00001164798	43113556	43113675
ENSE00001164807	43112853	43112963
ENSE00001164816	43112099	43112224
ENSE00001312192	43111207	43111465
ENSE00001365997	43100459	43100722
ENSE00001386034	43128112	43130351
ENSE00002442774	43123671	43123808
ENSE00002444663	43124883	43124982
ENSE00002515890	43121946	43122016
ENSE00004021789	43126575	43126722
ENSE00004021792	43119531	43119745
ENSE00004021793	43120081	43120203
ENSE00004021796	43077069	43077331

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 91.87.

FANTOM5 (CAGE): breadth broad, TPM avg 3.6163 / max 341.4287, expressed in 481 samples.

Highest expression (Bgee): substantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta, trigeminal ganglion, primordial germ cell in gonad.

Genetic regulation across tissues (GTEx eQTL / sQTL)

RET is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 31 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 32 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Adipose Visceral Omentum	eqtl	4.9e-13	+0.35	10:43075477:A:G
Adipose Subcutaneous	eqtl	2.2e-10	+0.30	10:43069900:C:A
Nerve Tibial	eqtl	2.5e-08	+0.28	10:43088591:A:T
Testis	eqtl	7.5e-08	-0.23	10:43077063:C:A
Skin Not Sun Exposed Suprapubic	eqtl	9.5e-07	-0.23	10:42945329:C:T
Lung	eqtl	1.1e-06	+0.26	10:43087702:A:G
Spleen	eqtl	5.8e-06	+0.48	10:43057483:C:T
Esophagus Mucosa	eqtl	8.8e-06	+0.23	10:43059238:T:C
Artery Tibial	eqtl	1.1e-05	+0.23	10:43097595:A:G
Ovary	eqtl	2.4e-05	+0.53	10:43088700:C:T
Skin Sun Exposed Lower leg	eqtl	3.1e-05	+0.18	10:43067728:C:A
Pancreas	eqtl	5.9e-05	-0.37	10:43090441:T:C
Stomach	eqtl	1.7e-04	+0.27	10:43097595:A:G
Thyroid	eqtl	1.9e-04	+0.24	10:43086825:A:C
Colon Transverse	eqtl	3.6e-04	+0.11	10:43101640:T:C
Muscle Skeletal	eqtl	2.3e-03	+0.15	10:42980205:G:T
Brain Cerebellum	eqtl	2.7e-03	+0.24	10:43080166:C:T
Artery Aorta	eqtl	2.9e-03	+0.23	10:43093126:G:C
Artery Coronary	eqtl	3.2e-03	+0.30	10:43084567:A:G
Esophagus Gastroesophageal Junction	eqtl	1.3e-02	+0.39	10:44024955:C:A

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
104739	3.6163	481

Top tissues by expression

showing 100 of 281 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
substantia nigra pars reticulata	UBERON:0001966	91.87	gold quality
dorsal root ganglion	UBERON:0000044	91.53	gold quality
substantia nigra pars compacta	UBERON:0001965	90.73	gold quality
trigeminal ganglion	UBERON:0001675	82.58	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.60	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.03	gold quality
substantia nigra	UBERON:0002038	80.27	gold quality
midbrain	UBERON:0001891	79.30	gold quality
pancreatic ductal cell	CL:0002079	78.66	silver quality
pons	UBERON:0000988	77.27	gold quality
tibialis anterior	UBERON:0001385	76.98	silver quality
endometrium epithelium	UBERON:0004811	76.11	gold quality
lateral nuclear group of thalamus	UBERON:0002736	74.36	gold quality
gingival epithelium	UBERON:0001949	73.98	gold quality
hindlimb stylopod muscle	UBERON:0004252	73.64	gold quality
primary visual cortex	UBERON:0002436	72.97	gold quality
superior vestibular nucleus	UBERON:0007227	72.79	gold quality
parotid gland	UBERON:0001831	72.60	silver quality
cerebellar vermis	UBERON:0004720	72.38	silver quality
superficial temporal artery	UBERON:0001614	72.12	gold quality
prefrontal cortex	UBERON:0000451	71.62	gold quality
ileal mucosa	UBERON:0000331	71.01	silver quality
hypothalamus	UBERON:0001898	70.96	gold quality
right adrenal gland	UBERON:0001233	70.50	gold quality
biceps brachii	UBERON:0001507	69.95	silver quality
stromal cell of endometrium	CL:0002255	69.84	gold quality
adrenal gland	UBERON:0002369	69.72	gold quality
left adrenal gland	UBERON:0001234	69.50	gold quality
right adrenal gland cortex	UBERON:0035827	69.37	gold quality
muscle layer of sigmoid colon	UBERON:0035805	69.25	gold quality
Brodmann (1909) area 9	UBERON:0013540	69.23	gold quality
left adrenal gland cortex	UBERON:0035825	68.83	gold quality
right frontal lobe	UBERON:0002810	68.55	gold quality
ventral tegmental area	UBERON:0002691	68.52	gold quality
pituitary gland	UBERON:0000007	68.39	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	68.28	gold quality
Brodmann (1909) area 23	UBERON:0013554	68.27	gold quality
frontal cortex	UBERON:0001870	68.00	gold quality
adenohypophysis	UBERON:0002196	67.98	gold quality
adrenal cortex	UBERON:0001235	67.92	gold quality
neocortex	UBERON:0001950	67.70	gold quality
occipital lobe	UBERON:0002021	67.68	gold quality
cingulate cortex	UBERON:0003027	67.61	gold quality
anterior cingulate cortex	UBERON:0009835	67.34	gold quality
gingiva	UBERON:0001828	67.20	gold quality
right hemisphere of cerebellum	UBERON:0014890	66.87	gold quality
skeletal muscle tissue	UBERON:0001134	66.67	gold quality
sigmoid colon	UBERON:0001159	66.64	gold quality
endothelial cell	CL:0000115	66.15	silver quality
muscle tissue	UBERON:0002385	65.71	gold quality
body of stomach	UBERON:0001161	65.64	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	65.43	silver quality
medulla oblongata	UBERON:0001896	65.27	gold quality
cerebellar cortex	UBERON:0002129	64.82	gold quality
rectum	UBERON:0001052	64.78	gold quality
germinal epithelium of ovary	UBERON:0001304	64.72	gold quality
colonic epithelium	UBERON:0000397	64.70	silver quality
cerebral cortex	UBERON:0000956	64.65	gold quality
cerebellum	UBERON:0002037	64.55	gold quality
cerebellar hemisphere	UBERON:0002245	64.55	gold quality
stomach	UBERON:0000945	64.49	gold quality
muscle organ	UBERON:0001630	64.36	gold quality
vermiform appendix	UBERON:0001154	64.10	gold quality
muscle of leg	UBERON:0001383	64.09	gold quality
upper leg skin	UBERON:0004262	63.90	gold quality
decidua	UBERON:0002450	63.71	silver quality
fundus of stomach	UBERON:0001160	63.66	gold quality
brain	UBERON:0000955	63.15	gold quality
lower esophagus muscularis layer	UBERON:0035833	63.09	gold quality
central nervous system	UBERON:0001017	63.08	gold quality
lower esophagus	UBERON:0013473	62.95	gold quality
cortical plate	UBERON:0005343	62.87	gold quality
middle temporal gyrus	UBERON:0002771	62.82	silver quality
colon	UBERON:0001155	62.78	gold quality
large intestine	UBERON:0000059	62.47	gold quality
Brodmann (1909) area 10	UBERON:0013541	62.39	gold quality
apex of heart	UBERON:0002098	62.37	gold quality
parietal pleura	UBERON:0002400	62.24	gold quality
forebrain	UBERON:0001890	62.11	gold quality
gastrocnemius	UBERON:0001388	62.07	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	62.05	gold quality
cranial nerve II	UBERON:0000941	61.76	silver quality
smooth muscle tissue	UBERON:0001135	61.75	gold quality
right lobe of liver	UBERON:0001114	61.53	gold quality
leukocyte	CL:0000738	61.49	gold quality
mononuclear cell	CL:0000842	61.47	gold quality
transverse colon	UBERON:0001157	61.38	gold quality
monocyte	CL:0000576	61.35	gold quality
testis	UBERON:0000473	61.34	gold quality
epithelium of nasopharynx	UBERON:0001951	61.30	gold quality
intestine	UBERON:0000160	61.27	gold quality
adipose tissue of abdominal region	UBERON:0007808	61.18	gold quality
spinal cord	UBERON:0002240	60.98	gold quality
telencephalon	UBERON:0001893	60.91	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	60.83	silver quality
inferior olivary complex	UBERON:0002127	60.78	silver quality
islet of Langerhans	UBERON:0000006	60.77	gold quality
omental fat pad	UBERON:0010414	60.70	gold quality
tendon of biceps brachii	UBERON:0008188	60.67	gold quality
peritoneum	UBERON:0002358	60.64	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	11.52
E-HCAD-25	yes	8.96
E-ANND-3	no	3.80

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 77 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Substantia nigra	tissue	86.5
Spinal cord	tissue	33.3
Locus coeruleus	tissue	30.4
Parathyroid gland	tissue	18.7	high
Medulla oblongata	tissue	12.9
Pons	tissue	12.8
Midbrain	tissue	12.7
Postcentral gyrus	tissue	11.9
Adrenal gland	tissue	10.9	not detected
Periaqueductal gray	tissue	9.4
Hypothalamus	tissue	8.5
Septum	tissue	6.6
Ventral forebrain	tissue	5.7
Olfactory bulb	tissue	5.1
Basal ganglia	tissue	4.9	medium
Hippocampal formation	tissue	4.7
Thalamus	tissue	3.8
Putamen	tissue	3.4
Superior colliculi	tissue	3.4
Salivary gland	tissue	3.2	medium
Skeletal muscle	tissue	3.0	not detected
Cerebral cortex	tissue	2.9	medium
Temporal cortex	tissue	2.9
Pituitary gland	tissue	2.2
Cerebellum	tissue	2.0	low
Hippocampus	tissue	2.0	medium
Caudate putamen	tissue	2.0
Tongue	tissue	1.9
Testis	tissue	1.8	medium
Retina	tissue	1.8
Amygdala	tissue	1.8
Choroid plexus	tissue	1.7
Frontal cortex	tissue	1.5
Nucleus accumbens	tissue	1.5
Adipose tissue	tissue	1.4	not detected
Insular cortex	tissue	1.3
Seminal vesicle	tissue	1.2	not detected
Stomach 1	tissue	1.1	low
Duodenum	tissue	1.0	medium
Prostate	tissue	1.0	medium
Thymus	tissue	1.0
Colon	tissue	0.9	low
Liver	tissue	0.9	low
Small intestine	tissue	0.9	medium
Entorhinal cortex	tissue	0.9
Appendix	tissue	0.9	low
Prefrontal cortex	tissue	0.8
Rectum	tissue	0.8	not detected
Somatosensory cortex	tissue	0.8
Motor cortex	tissue	0.7
Retrosplenial and cingulate cortex	tissue	0.7
Retrosplenial cortex	tissue	0.7
Occipital cortex	tissue	0.7
Vagina	tissue	0.6	not detected
Smooth muscle	tissue	0.5	not detected
Urinary bladder	tissue	0.5	not detected
Lymph node	tissue	0.4	low
Pancreas	tissue	0.4	medium
Endometrium 1	tissue	0.4	not detected
Gallbladder	tissue	0.4	medium

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Ventral tegmental area (57.7), Median raphe nucleus (38.1), Motor hypoglossal nucleus (36.5), Spinal trigeminal nucleus, interpolar (35.6), Ventral spinal cord (33.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ASCL1, CTNNB1, EGR1, EGR2, ESR1, FOXA1, FOXC1, HOXB5, NKX2-1, NR4A2, PAX2, PAX3, PAX8, PHOX2A, PHOX2B, PREB, RARG, RUNX1, SOX10, SP1, SP3, TFAP2A, TFAP2C, TFCP2, TLX2, TTF1

miRNA regulators (miRDB)

Targeting RET by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 105 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.24, missense Z 2.69 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000355710 splits into 5 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
10:43,077,259–43,100,467	38 / 33.1	1.15	no
10:43,100,468–43,102,440	84 / 163.6	0.51	no
10:43,102,441–43,119,709	850 / 969.6	0.88	no
10:43,119,710–43,123,797	73 / 156.5	0.47	no
10:43,123,798–43,128,266	174 / 179.3	0.97	no
ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• The presence of coiled-coil domains in the ktn1/ret fusion protein (PTC8) suggests ligand-independent dimerization and thus constitutive activation of the ret tyrosine kinase domain. (PMID:10850414)
• Three new somatic cell missense mutations of the RET proto-oncogene associated with sporadic medullary thyroid carcinoma (MTC). (PMID:11692159)
• A germline RET mutation at codon 603 in exon 10 is associated with both medullary and nonmedullary thyroid cancer in a kindred. (PMID:11746981)
• Differentiation of cardiac ganglionic cells is affected, after RETINOIC ACID treatment, by the down-regulation of c-Ret. (PMID:11803116)
• RET oligonucleotide microarray for the detection of RET mutations in multiple endocrine neoplasia type 2 syndromes (PMID:11839664)
• The finding of a somatic deletion in RET exon 15 clarified the sporadic nature of a medullary thyroid carcinoma suspected to be familial. A 12 bp deletion within the catalytic domain of the protooncogene RET. (PMID:11883863)
• role in regulating rac activity and lamellipodia formation (PMID:11886862)
• early detection of RET proto-oncogene mutation is crucial for prevention of thyroidectomy in multiple endocrine neoplasia type 2 children (PMID:11900218)
• if the association between Hashimoto’s thyroiditis and thyroid cancer exists, its molecular basis is different from RET/PTC rearrangement (PMID:11927965)
• Familial medullary thyroid carcinoma: clinical variability and low aggressiveness associated with RET mutation at codon 804. (PMID:11932300)
• family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. polymorphic sequence variants of the RET proto-oncogene. (PMID:11935126)
• germline mutation of the RET proto-oncogene in members of Slovak families with multiple endocrine neoplasia 2 (PMID:11949835)
• Segregation at three loci explains familial and population risk in Hirschsprung disease. We show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET. (PMID:11953745)
• Dissecting Hirschsprung disease. RET is the main gene conferring susceptibility. (PMID:11953748)
• These observations lend support to the idea that both RET alleles have a role in pathogenesis of Hirschsprung’s disease, in a dose-dependent fashion. We also showed that the c135G/A polymorphism modifies the phenotype. (PMID:11955539)
• Hirschsprung associated GDNF mutations do not prevent RET activation (PMID:11973622)
• the G691S and S904S variants of RET may somehow play a role on the age of onset of MEN 2A (PMID:11979448)
• Activation of RET tyrosine kinase regulates interleukin-8 production by multiple signaling pathways (PMID:12056817)
• RET activation closely parallels the morphological changes, that it is restricted to those areas of the tumor with the cytological alterations and that it is detectable in both mono- and polyclonal tumors (PMID:12057919)
• RET codon 691 polymorphism is associated with radiation induced tumors with a C-cell hyperplasia of thyroid tumors (PMID:12085189)
• RET/PTC rearrangement in thyroid tumors. Review (PMID:12114746)
• RET expression in papillary thyroid cancer from patients irradiated in childhood for benign conditions. (PMID:12161537)
• Analysis of mutation of protooncogene RET are presented in patients with thyroid medullary carcinoma (PMID:12182057)
• analysis of RET somatic mutations supports the differentiation between sporadic and inherited medullary thyroid carcinoma (PMID:12182058)
• 5’-End RET splicing: absence of variants in normal tissues and intron retention in pheochromocytomas. (PMID:12187076)
• Possible pathogenesis of papillary thyroid carcinoma caused by exon 13 and 14 RET mutations that affect the intracellular domain of ret proto-oncogene protein. (PMID:12193298)
• a protective role of this low-penetrant haplotype in the pathogenesis of HSCR and demonstrate a possible functional effect linked to RET messenger RNA expression. (PMID:12214285)
• genetic interaction between mutations in RET and EDNRB is an underlying mechanism for Hirschsprung disease (PMID:12355085)
• relationship between RET oncogene and Chinese patients with Hirschsprung’s disease (PMID:12439935)
• A novel Val648Ile substitution in RET protooncogene observed in a Cys634Arg multiple endocrine neoplasia type 2A kindred presenting with an adrenocorticotropin-producing pheochromocytoma. (PMID:12466368)
• A founding locus within the RET proto-oncogene may account for a large proportion of apparently sporadic Hirschsprung disease and a subset of cases of sporadic medullary thyroid carcinoma (PMID:12474140)
• Patients with RET codon 790/791 mutations seemed to have a less aggressive clinical course compared with patients with classic multiple endocrine neoplasia type 2A syndrome. (PMID:12490841)
• Amplification and overexpression of mutant RET in multiple endocrine neoplasia type 2-associated medullary thyroid carcinoma. RET germline mutation in codon 634. Tandem duplication.Genomic chromosome 10 abnormalities increase mutant RET mRNA. (PMID:12519890)
• RET proto-oncogene is often stimulated in follicular cell-derived thyroid tumors, not only in papillary carcinoma but also in follicular tumors (follicular adenomas and follicular carcinoma), and may contribute to tumorigenesis of these tumors. (PMID:12608895)
• Not only RET mutations but also RET polymorphic variants may contribute to the occurrence of total intestinal aganglionosis. (PMID:12632375)
• RET/PTC associates with STAT3 and activates it by the specific phosphorylation of the tyrosine 705 residue. STAT3 activation by the RET/PTC tyrosine kinase is one of the critical signaling pathways for the regulation of specific genes. (PMID:12637586)
• High prevalence of BRAF mutations in thyroid cancer is genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. (PMID:12670889)
• in RET mutation carriers in Hirschsprung’s disease, the gut caliber change was almost identical to the histologic transition in cases of short segment aganglionosis, whereas these were markedly dissociated in cases exhibiting extensive aganglionosis (PMID:12720173)
• RET rearrangements may not play any distinctive role in driving histotype development and cancer progression in papillary thyroid carcinomas. (PMID:12720532)
• A deletion of the chromosomal region including the RET proto-oncogene is involved in the pathogenesis of SCLC (PMID:12767512)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ret	ENSDARG00000055305
mus_musculus	Ret	ENSMUSG00000030110
rattus_norvegicus	Ret	ENSRNOG00000014751
drosophila_melanogaster	Ret	FBGN0011829

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), EPHA3 (ENSG00000044524), ROS1 (ENSG00000047936), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), EPHA6 (ENSG00000080224), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), EPHB2 (ENSG00000133216), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), ERBB2 (ENSG00000141736), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), RYK (ENSG00000163785), MST1R (ENSG00000164078), LMTK2 (ENSG00000164715), AXL (ENSG00000167601), ROR2 (ENSG00000169071), ALK (ENSG00000171094), INSR (ENSG00000171105), ERBB4 (ENSG00000178568), CSF1R (ENSG00000182578), EPHB3 (ENSG00000182580), EPHA10 (ENSG00000183317), ROR1 (ENSG00000185483), EPHB4 (ENSG00000196411), NTRK1 (ENSG00000198400), DDR1 (ENSG00000204580)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97902) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 116 distinct phenotype terms.

Mouse phenotype (MP)	Records
absent kidney	9
absent enteric neurons	8
abnormal enteric ganglia morphology	6
neonatal lethality, complete penetrance	6
abnormal enteric neuron morphology	5
abnormal colon morphology	3
abnormal kidney development	3
abnormal ureter morphology	3
abnormal enteric nervous system morphology	3
abnormal kidney morphology	3
intestinal hypoperistalsis	3
kidney cyst	3
decreased renal glomerulus number	3
abnormal small intestine morphology	2
abnormal sympathetic ganglion morphology	2
distended abdomen	2
increased pheochromocytoma incidence	2
premature death	2
abnormal neuron morphology	2
increased neuron apoptosis	2
renal hypoplasia	2
single kidney	2
absent ureter	2
impaired branching involved in ureteric bud morphogenesis	2
abnormal ureteric bud morphology	2

+91 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pan troglodytes	Q7YR43	99.6%	Diamond
Bos taurus	P43481	99.4%	Diamond
Capra hircus	Q28317	99.4%	Diamond
Macaca fascicularis	Q5IFJ9	99.4%	Diamond
Macaca mulatta	P55245	99.3%	Diamond
Felis catus	Q28889	99.2%	Diamond
Saimiri boliviensis boliviensis	Q5IS82	99.0%	Diamond
Gallus gallus	P08941	98.7%	Diamond
Canis lupus familiaris	O97799	98.4%	Diamond
Sus scrofa	Q2HWD6	98.1%	Diamond
Xenopus tropicalis	A0JM20	95.5%	Diamond
Xenopus laevis	Q8QFP9	95.5%	Diamond
Callithrix jacchus	Q76II0	94.6%	Diamond
Mesocricetus auratus	Q60553	90.3%	Diamond
Avian leukosis virus	P00534	100.0%	Diamond
Avian erythroblastosis virus (strain ts167)	P11273	100.0%	Diamond
Avian erythroblastosis virus (strain ES4)	P00535	99.5%	Diamond
Feline sarcoma virus (STRAIN HARDY-ZUCKERMAN 4)	P04048	99.2%	Diamond
Feline sarcoma virus (STRAIN MCDONOUGH)	P00545	99.1%	Diamond
UR2 sarcoma virus	P00529	98.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
LINC02623	ncRNA	101929445
LINC01264	ncRNA	104266963
CSGALNACT2-DT	ncRNA	118568825
MIR5100	ncRNA	100847014
BMS1	protein-coding	9790
CSGALNACT2	protein-coding	55454
RASGEF1A	protein-coding	221002
LINC02633	ncRNA	105378270

Protein

Protein identifiers

Proto-oncogene tyrosine-protein kinase receptor Ret — P07949 (reviewed: P07949)

Alternative names: Cadherin family member 12, Proto-oncogene c-Ret

All UniProt accessions (10): A0A087WWB1, A0A1W2PPN7, A0A1W2PSA1, A0A5F9ZHB7, A0A5F9ZHR6, A0A804HIK7, A0A804HL71, A0AAQ5BH28, C9JYL6, P07949

UniProt curated annotations — full annotation on UniProt →

Function. Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN, ARTN, PSPN and GDF15). In contrast to most receptor tyrosine kinases, RET requires not only its cognate ligands but also coreceptors, for activation. GDNF ligands (GDNF, NRTN, ARTN, PSPN and GDF15) first bind their corresponding GDNFR coreceptors (GFRA1, GFRA2, GFRA3, GFRA4 and GFRAL, respectively), triggering RET autophosphorylation and activation, leading to activation of downstream signaling pathways, including the MAPK- and AKT-signaling pathways. Acts as a dependence receptor via the GDNF-GFRA1 signaling: in the presence of the ligand GDNF in somatotrophs within pituitary, promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Required for the molecular mechanisms orchestration during intestine organogenesis via the ARTN-GFRA3 signaling: involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer’s patch-like structures, a major component of the gut-associated lymphoid tissue. Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which triggers an aversive response, characterized by nausea, vomiting, and/or loss of appetite in response to various stresses. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Also active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Involved in the development of the neural crest. Regulates nociceptor survival and size. Phosphorylates PTK2/FAK1. Isoform 1 in complex with GFRAL induces higher activation of MAPK-signaling pathway than isoform 2 in complex with GFRAL.

Subunit / interactions. Phosphorylated form interacts with the PBT domain of DOK2, DOK4 and DOK5. The phosphorylated form interacts with PLCG1 and GRB7. Interacts (not phosphorylated) with PTK2/FAK1 (via FERM domain). Extracellular cell-membrane anchored RET cadherin fragments form complex in neurons with reduced trophic status, preferentially at the contact sites between somas. Interacts with AIP in the pituitary gland; this interaction prevents the formation of the AIP-survivin complex. Interacts (inactive) with CBLC and CD2AP; dissociates upon activation by GDNF which increases CBLC:CD2AP interaction.

Subcellular location. Cell membrane. Endosome membrane.

Post-translational modifications. Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation. Proteolytically cleaved by caspase-3. The soluble RET kinase fragment is able to induce cell death. The extracellular cell-membrane anchored RET cadherin fragment accelerates cell adhesion in sympathetic neurons.

Disease relevance. Hirschsprung disease 1 (HSCR1) [MIM:142623] A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. The disease is caused by variants affecting the gene represented in this entry. Medullary thyroid carcinoma (MTC) [MIM:155240] Rare tumor derived from the C cells of the thyroid. Three hereditary forms are known, that are transmitted in an autosomal dominant fashion: (a) multiple neoplasia type 2A (MEN2A), (b) multiple neoplasia type IIB (MEN2B) and (c) familial MTC (FMTC), which occurs in 25-30% of MTC cases and where MTC is the only clinical manifestation. The disease is caused by variants affecting the gene represented in this entry. Multiple neoplasia 2B (MEN2B) [MIM:162300] Uncommon inherited cancer syndrome characterized by predisposition to MTC and phaeochromocytoma which is associated with marfanoid habitus, mucosal neuromas, skeletal and ophthalmic abnormalities, and ganglioneuromas of the intestine tract. Then the disease progresses rapidly with the development of metastatic MTC and a pheochromocytome in 50% of cases. The disease is caused by variants affecting the gene represented in this entry. Pheochromocytoma (PCC) [MIM:171300] A catecholamine-producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. Disease susceptibility is associated with variants affecting the gene represented in this entry. Multiple neoplasia 2A (MEN2A) [MIM:171400] The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. The disease is caused by variants affecting the gene represented in this entry. Various chromosomal aberrations involving RET are known. Some of them have been found in papillary thyroid carcinomas (PTCs). Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene. Inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene. Translocation t(10;14)(q11;q32) with GOLGA5 generates the RET/GOLGA5 (PTC5) oncogene. Translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion. Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the Delta RFP/RET oncogene. Translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene. Translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene. Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the TRIM27/RET oncogene. Mutations in RET have been detected in patients with renal agenesis suggesting a possible involvement of this gene in disease pathogenesis.

Activity regulation. Repressed by 4-(3-hydroxyanilino)-quinolines derivatives, indolin-2-one-derivatives, 2-(alkylsulfanyl)-4-(3-thienyl) nicotinonitrile analogs, 3- and 4-substituted beta-carbolin-1-ones, vandetanib, motesanib, sorafenib (BAY 43-9006), cabozantinib (XL184), lenvatinib, sunitinib, nintedanib, and withaferin A (WA). Inactivation by sorafenib both reduces kinase activity and promotes lysosomal degradation.

Induction. Positively regulated by NKX2-1, PHOX2B, SOX10 and PAX3.

Miscellaneous. Treatment with withaferin A (WA) leads tumor regression in medullary thyroid carcinomas (MTC).

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P07949-1	1, RET51	yes
P07949-2	2, RET9

RefSeq proteins (41): NP_001342145, NP_001393672, NP_001393673, NP_001393688, NP_001393689, NP_001393690, NP_001393691, NP_001393692, NP_001393693, NP_001393694, NP_001393695, NP_001393696, NP_001393697, NP_001393698, NP_001393699, NP_001393700, NP_001393701, NP_001393702, NP_001393703, NP_001393704, NP_001393705, NP_001393706, NP_001393707, NP_001393708, NP_001393709, NP_001393710, NP_001393711, NP_001393712, NP_001393713, NP_001393714, NP_001393715, NP_001393716, NP_001393717, NP_001393718, NP_001393719, NP_001393720, NP_001393721, NP_001393722, NP_001393723, NP_065681, NP_066124* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR002126	Cadherin-like_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR015919	Cadherin-like_sf	Homologous_superfamily
IPR016249	Tyr_kinase_Ret_rcpt	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR040667	Ret_CLD3	Domain
IPR041163	Ret_CLD1	Domain
IPR041317	RET_CLD4	Domain
IPR050122	RTK	Family
IPR055162	RET_CRD	Domain

Pfam: PF00028, PF07714, PF17756, PF17812, PF17813, PF22540

Enzyme classification (BRENDA)

• EC 2.7.10.1 — receptor protein-tyrosine kinase (BRENDA: 44 organisms, 214 substrates, 574 inhibitors, 11 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0011–0.129	4
AC-DYFE-6-CHLORO-W-NHME	0.0051	1
AC-DYFGW-NHME	0.07	1
YFEW	0.232	1

Catalyzed reactions (Rhea)

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (299 total): sequence variant 148, strand 26, helix 25, binding site 24, modified residue 13, glycosylation site 13, disulfide bond 13, mutagenesis site 10, turn 5, sequence conflict 4, site 4, chain 3, region of interest 3, topological domain 2, domain 2, signal peptide 1, active site 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

showing 30 of 34 structures by resolution:

PDB	Title	Method	Resolution (Å)
7DUA	Crystal structure of human Proto-oncogene tyrosine-protein kinase receptor Ret in complex …	X-RAY DIFFRACTION	1.64
4CKJ	Crystal structure of RET tyrosine kinase domain bound to adenosine	X-RAY DIFFRACTION	1.65
6NEC	STRUCTURE OF RET PROTEIN TYROSINE KINASE DOMAIN IN COMPLEX WITH NINTEDANIB	X-RAY DIFFRACTION	1.87
6I83	Crystal structure of phosphorylated RET V804M tyrosine kinase domain complexed with …	X-RAY DIFFRACTION	1.88
7JU5	Structure of RET protein tyrosine kinase in complex with pralsetinib	X-RAY DIFFRACTION	1.9
6NJA	Structure of WT RET protein tyrosine kinase domain at 1.92A resolution.	X-RAY DIFFRACTION	1.92
6NE7	Structure of G810A mutant of RET protein tyrosine kinase domain.	X-RAY DIFFRACTION	1.99
2IVS	Crystal structure of non-phosphorylated RET tyrosine kinase domain	X-RAY DIFFRACTION	2
2X2L	Crystal Structure of phosphorylated RET tyrosine kinase domain with inhibitor	X-RAY DIFFRACTION	2
2X2U	First two Cadherin-like domains from Human RET	X-RAY DIFFRACTION	2
6I82	Crystal structure of partially phosphorylated RET V804M tyrosine kinase domain complexed …	X-RAY DIFFRACTION	2.05
7JU6	Structure of RET protein tyrosine kinase in complex with selpercatinib	X-RAY DIFFRACTION	2.06
4CKI	Crystal Structure of oncogenic RET tyrosine kinase M918T bound to adenosine	X-RAY DIFFRACTION	2.12
2IVV	Crystal structure of phosphorylated RET tyrosine kinase domain complexed with the …	X-RAY DIFFRACTION	2.25
6FEK	Oncogenic point mutation of RET receptor tyrosine kinase	X-RAY DIFFRACTION	2.3
6VHG	Crystal structure of phosphorylated RET tyrosine kinase domain complexed with a …	X-RAY DIFFRACTION	2.3
7DU9	Crystal structure of human Proto-oncogene tyrosine-protein kinase receptor Ret in complex …	X-RAY DIFFRACTION	2.31
7NZN	Structure of RET kinase domain bound to inhibitor JB-48	X-RAY DIFFRACTION	2.39
2IVU	Crystal structure of phosphorylated RET tyrosine kinase domain complexed with the …	X-RAY DIFFRACTION	2.5
2X2M	Crystal Structure of phosphorylated RET tyrosine kinase domain with inhibitor	X-RAY DIFFRACTION	2.5
5AMN	The Discovery of 2-Substituted Phenol Quinazolines as Potent and Selective RET Kinase …	X-RAY DIFFRACTION	2.57
2IVT	Crystal structure of phosphorylated RET tyrosine kinase domain	X-RAY DIFFRACTION	2.6
2X2K	Crystal Structure of phosphorylated RET tyrosine kinase domain with inhibitor	X-RAY DIFFRACTION	2.6
7DU8	Crystal structure of human Proto-oncogene tyrosine-protein kinase receptor Ret in complex …	X-RAY DIFFRACTION	2.75
5FM3	Crystal structure of hyper-phosphorylated RET kinase domain with (proximal) juxtamembrane …	X-RAY DIFFRACTION	2.95
5FM2	Crystal structure of hyper-phosphorylated RET kinase domain with (proximal) juxtamembrane …	X-RAY DIFFRACTION	3.3
7RUN	Crystal structure of phosphorylated RET tyrosine kinase domain complexed with a …	X-RAY DIFFRACTION	3.51
6Q2O	Cryo-EM structure of RET/GFRa2/NRTN extracellular complex. The 3D refinement was applied …	ELECTRON MICROSCOPY	3.65
6Q2S	Cryo-EM structure of RET/GFRa3/ARTN extracellular complex. The 3D refinement was applied …	ELECTRON MICROSCOPY	3.8
6Q2J	Cryo-EM structure of extracellular dimeric complex of RET/GFRAL/GDF15	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07949-F1	79.27	0.52

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, Tyr protein kinases, Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes, Congenital malformations, Congenital malformations of the digestive system

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; golgi apparatus; plasma membrane

Antibody reliability (HPA): IH approved · IF approved

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (5)

Position	Role
874	proton acceptor
587–588	breakpoint for translocation to form the trim27/ret oncogene
707–708	cleavage; by caspase-3
712–713	breakpoint for translocation to form pcm1-ret; ret-ccdc6; ret-golga5; ret-trim24 and ret-trim33 oncogenes
1017–1018	cleavage; by caspase-3

Ligand- & substrate-binding residues (24)

Position	Role
178	Ca(2+)
179	Ca(2+)
230	Ca(2+)
232	Ca(2+)
264	Ca(2+)
265	Ca(2+)
266	Ca(2+)
267	Ca(2+)
268	Ca(2+)
300	Ca(2+)
302	Ca(2+)
378	Ca(2+)
564	Ca(2+)
565	Ca(2+)
567	Ca(2+)
569	Ca(2+)
574	Ca(2+)
584	Ca(2+)
730–738	ATP
758	ATP
805–807	semaxanib

Post-translational modifications (13)

Type	Positions
Phosphotyrosine	687, 806, 809, 826, 900, 905, 981, 1015, 1029, 1062, 1090, 1096
Phosphoserine	696

Disulfide bonds (13)

Type	Positions
Disulfide bond	137–142, 157–197, 166–243, 426–430, 449–478, 515–531, 519–541, 528–558, 565–581, 570–585, 609–620, 611–618, 630–634

Glycosylation sites (13)

Type	Positions
N-linked (glcnac…) asparagine	98, 151, 199, 336, 343, 361, 367, 377, 394, 448, 468, 554
O-linked (glcnac) serine	688

Mutagenesis-validated functional residues (10)

Position	Phenotype
36	defects in maturation and processing.
41	defects in maturation and processing.
85	defects in maturation and processing.
707	impaired cleavage by caspase-3 and loss of induced cell death.
708–1114	loss of induced cell death, but increased cell aggregation.
734	enhanced protein autophosphorylation due to enhanced substrate presentation in trans.
758	loss of kinase activity. no effect on interaction with and dissociation from cblc and cd2ap.
912	enhanced protein autophosphorylation due to enhanced substrate presentation in trans.
913	enhanced protein autophosphorylation due to enhanced substrate presentation in trans.
1062	abolishes gfral-mediated mapk1/mapk2 phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 16; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

16 pathways:

ID	Pathway	Evidence
R-HSA-9768919	NPAS4 regulates expression of target genes	curated
R-HSA-5673001	RAF/MAP kinase cascade	curated
R-HSA-8853659	RET signaling	curated
R-HSA-422475	Axon guidance	—
R-HSA-1266738	Developmental Biology	—
R-HSA-9830364	Formation of the nephric duct	electronic
R-HSA-9830674	Formation of the ureteric bud	electronic
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-9830369	Kidney development	—
R-HSA-5683057	MAPK family signaling cascades	—
R-HSA-5684996	MAPK1/MAPK3 signaling	—
R-HSA-9675108	Nervous system development	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-162582	Signal Transduction	—
R-HSA-9634815	Transcriptional Regulation by NPAS4	—

MSigDB gene sets: 586 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, TGGTGCT_MIR29A_MIR29B_MIR29C, ELVIDGE_HYPOXIA_DN, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_URETER_DEVELOPMENT, GOBP_METANEPHROS_DEVELOPMENT, E2F4DP1_01, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, PEREZ_TP63_TARGETS, GOBP_NEURON_MATURATION, GOZGIT_ESR1_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_KIDNEY_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY

GO Biological Process (25): homophilic cell-cell adhesion (GO:0007156), neuron cell-cell adhesion (GO:0007158), signal transduction (GO:0007165), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), axon guidance (GO:0007411), posterior midgut development (GO:0007497), positive regulation of neuron projection development (GO:0010976), regulation of cell adhesion (GO:0030155), positive regulation of cell migration (GO:0030335), membrane protein proteolysis (GO:0033619), positive regulation of cell adhesion mediated by integrin (GO:0033630), glial cell-derived neurotrophic factor receptor signaling pathway (GO:0035860), positive regulation of MAPK cascade (GO:0043410), positive regulation of DNA-templated transcription (GO:0045893), response to pain (GO:0048265), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), Peyer’s patch morphogenesis (GO:0061146), cellular response to retinoic acid (GO:0071300), positive regulation of metanephric glomerulus development (GO:0072300), lymphocyte migration into lymphoid organs (GO:0097021), GDF15-GFRAL signaling pathway (GO:0160144), positive regulation of extrinsic apoptotic signaling pathway in absence of ligand (GO:2001241), protein phosphorylation (GO:0006468), cell adhesion (GO:0007155), nervous system development (GO:0007399)

GO Molecular Function (10): protein tyrosine kinase activity (GO:0004713), transmembrane receptor protein tyrosine kinase activity (GO:0004714), calcium ion binding (GO:0005509), ATP binding (GO:0005524), signaling receptor activity (GO:0038023), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (6): plasma membrane (GO:0005886), endosome membrane (GO:0010008), axon (GO:0030424), signaling receptor complex (GO:0043235), plasma membrane protein complex (GO:0098797), membrane (GO:0016020)

Reactome top-level categories

11 top-level categories:

Category	Pathways
Kidney development	2
Developmental Biology	2
MAPK1/MAPK3 signaling	1
Axon guidance	1
Transcriptional Regulation by NPAS4	1
RNA Polymerase II Transcription	1
Nervous system development	1
Signal Transduction	1
MAPK family signaling cascades	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1

GO top-level categories

showing 60 of 68 GO namespaces:

Category	Terms
cell-cell adhesion	2
regulation of cellular process	2
positive regulation of intracellular signal transduction	2
cell communication	1
cellular process	1
signaling	1
cellular response to stimulus	1
enzyme-linked receptor protein signaling pathway	1
axonogenesis	1
neuron projection guidance	1
midgut development	1
animal gross anatomical part developmental process	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
cell adhesion	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
proteolysis	1
cell adhesion mediated by integrin	1
regulation of cell adhesion mediated by integrin	1
positive regulation of cell adhesion	1
cell surface receptor protein tyrosine kinase signaling pathway	1
MAPK cascade	1
regulation of MAPK cascade	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
multicellular organismal response to stress	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
Peyer’s patch development	1
tissue morphogenesis	1
response to retinoic acid	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
positive regulation of metanephros development	1
metanephric glomerulus development	1
regulation of metanephric glomerulus development	1
positive regulation of glomerulus development	1
lymphocyte migration	1
protein kinase activity	1
protein tyrosine kinase activity	1
transmembrane receptor protein kinase activity	1
metal ion binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
molecular transducer activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
membrane	1
cell periphery	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 18 of 41 annotations. The rest are phylogenetic / computational / electronic (IEA).

18 experimentally-supported GO terms:

GO term	NS	Evidence
GDF15-GFRAL signaling pathway	BP	direct assay
cellular response to retinoic acid	BP	mutant phenotype
glial cell-derived neurotrophic factor receptor signaling pathway	BP	direct assay
membrane protein proteolysis	BP	direct assay
neuron cell-cell adhesion	BP	mutant phenotype
positive regulation of MAPK cascade	BP	direct assay
positive regulation of cell adhesion mediated by integrin	BP	direct assay
positive regulation of cell migration	BP	direct assay
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	BP	mutant phenotype
positive regulation of neuron projection development	BP	mutant phenotype
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	BP	mutant phenotype
regulation of cell adhesion	BP	direct assay
endosome membrane	CC	direct assay
plasma membrane	CC	direct assay
plasma membrane protein complex	CC	direct assay
signaling receptor complex	CC	direct assay
calcium ion binding	MF	direct assay
transmembrane receptor protein tyrosine kinase activity	MF	direct assay

Protein interactions and networks

STRING

showing 14 of 3,420 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RET	GDNF	P39905	948
RET	GFRA1	P56159	942
RET	NRTN	Q99748	923
RET	SDHD	O14521	900
RET	NCOA4	Q13772	894
RET	TMEM127	O75204	893
RET	NCOA4	Q13772	892
RET	SDHB	P21912	886
RET	ARTN	Q5T4W7	878
RET	MPST	P25325	876
RET	PSPN	O60542	872
RET	PTCH1	Q13635	856
RET	GFRA2	O00451	843
RET	NF1	P21359	841

IntAct

Human interaction partners of RET in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 33 partners by confidence:

Partner	Interaction type	MIscore	Records
CBL	physical association	0.700	8
TLN1	direct interaction	0.620	2
NOTCH2NLA	physical association	0.560	3
EGFR	physical association	0.550	2
ALK	physical association	0.500	1
FGFR4	physical association	0.500	1
PLCG1	proximity	0.480	3
STAT3	proximity	0.480	3
FAU	covalent binding	0.440	4
GAS1	direct interaction	0.440	1
LRRK1	direct interaction	0.440	1
PKM	phosphorylation reaction	0.440	1
CTNND1	physical association	0.400	1
GFRA1	physical association	0.400	1
GRB2	physical association	0.400	1
LRIG1	physical association	0.400	1
SHC1	physical association	0.400	1
PTPRR	physical association	0.370	2
DUSP26	physical association	0.370	1
PIK3R2	association	0.350	1
SOS1	association	0.350	1
SRC	association	0.350	1
SRY	association	0.350	1
TIMP1	association	0.350	1
ZBTB48	association	0.350	1
BRAF	proximity	0.270	1
CRK	proximity	0.270	1
MAPK1	proximity	0.270	1
MAPK3	proximity	0.270	1
NUDT19	proximity	0.270	1

BioGRID (351 interactions; top human partners by supporting records): CBL (Affinity Capture-Western; 6 records), GRB10 (Reconstituted Complex; 6 records), AIP (PCA; 5 records), GRB2 (Reconstituted Complex; 5 records), SHC1 (Affinity Capture-Western; 5 records), CBLC (Affinity Capture-Western; 4 records), EGFR (Two-hybrid; 4 records), STAT3 (Co-localization; 4 records), CACYBP (Affinity Capture-Western; 3 records), CRK (Co-localization; 3 records), CTNNB1 (Affinity Capture-Western; 3 records), DOK1 (Two-hybrid; 3 records), DOK5 (Affinity Capture-Western; 3 records), HSP90AA1 (Cross-Linking-MS (XL-MS); 3 records), NEDD4 (Reconstituted Complex; 3 records)

SIGNOR signaling

showing 35 of 68 signaling interactions:

A	Effect	B	Mechanism
RET	up-regulates	FRS2	binding
RET	up-regulates	DOK4	binding
RET	up-regulates	DOK5	binding
RET	up-regulates	RET	phosphorylation
RET	up-regulates	DOK6	binding
RET	up-regulates	MAPK1	phosphorylation
RET	up-regulates	MAPK3	phosphorylation
PTPRJ	down-regulates	RET	dephosphorylation
RET	up-regulates	MAPK14	phosphorylation
RET	up-regulates	AKT	phosphorylation
PRKACA	down-regulates	RET	phosphorylation
PTK2	up-regulates	RET	phosphorylation
RET	up-regulates	PTK2	phosphorylation
motesanib	down-regulates	RET	“chemical inhibition”
TG101209	down-regulates	RET	“chemical inhibition”
RET	up-regulates	ERK1/2	phosphorylation
PTPRJ	“down-regulates activity”	RET	dephosphorylation
RET	up-regulates	AKT1	phosphorylation
lapatinib	“down-regulates activity”	RET	“chemical inhibition”
regorafenib	“down-regulates activity”	RET	“chemical inhibition”
ponatinib	“down-regulates activity”	RET	“chemical inhibition”
cabozantinib	“down-regulates activity”	RET	“chemical inhibition”
RET	“up-regulates activity”	AFAP1L2	phosphorylation
RET	up-regulates	Gbeta	phosphorylation
RET	“down-regulates quantity by destabilization”	ATF4	phosphorylation
CBLC	“down-regulates quantity by destabilization”	RET	ubiquitination
RET	“up-regulates activity”	PRKDC	phosphorylation
RET	“up-regulates activity”	STAT1	phosphorylation
RET	“down-regulates activity”	ATF4	phosphorylation
RET	up-regulates	SHC1	binding
RET	up-regulates	GRB10	binding
RET	up-regulates	GRB7	binding
GDNF	up-regulates	RET	binding
NRTN	up-regulates	RET	binding
RET	up-regulates	GFRA1	binding

Protein complexes (CORUM) (8)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

8 complexes by size:

Complex	Subunits	Members
★ GDF15-GFRAL-RET complex	3	GDF15, GFRAL, RET
★ GFRA1-RET-SORL1 complex	3	GFRA1, RET, SORL1
★ GDNF-GFRA1-RET complex	3	GDNF, GFRA1, RET
★ GFRA2-NRTN-RET complex	3	RET, GFRA2, NRTN
★ ARTN-GFRA3-RET comples	3	ARTN, GFRA3, RET
★ AIP-RET complex	2	AIP, RET
★ MET-RET complex	2	MET, RET
★ RET-Rai complex	2	RET, SHC3

Ligand–receptor pairs (CellPhoneDB) (4)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

4 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
RET;GFRA4		Signaling by RET receptors
RET;GFRA3		Signaling by RET receptors
RET;GFRA2		Signaling by Neurotrophin
RET;GFRA1		Signaling by RET receptors

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Spry regulation of FGF signaling	6	147.7×	2e-10
Constitutive Signaling by EGFRvIII	6	147.7×	2e-10
GRB2:SOS provides linkage to MAPK signaling for Integrins	5	123.1×	9e-09
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	6	118.1×	6e-10
Signaling by ALK	6	118.1×	6e-10
Insulin receptor signalling cascade	5	115.8×	1e-08
Signaling by ERBB2 ECD mutants	5	115.8×	1e-08
Signalling to ERKs	5	103.6×	2e-08

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	10	75.1×	3e-14
insulin-like growth factor receptor signaling pathway	5	75.1×	1e-06
insulin receptor signaling pathway	6	40.3×	1e-06
regulation of cell population proliferation	5	17.5×	4e-04
positive regulation of ERK1 and ERK2 cascade	5	12.9×	9e-04
cell migration	6	11.2×	5e-04
negative regulation of apoptotic process	7	7.4×	9e-04

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

RET mutations and the RET fusion RET-PTC lead to activation of this tyrosine kinase receptor and are associated with thyroid cancers. RET point mutations are the most common mutations identified in medullary thyroid cancer (MTC) with germline and somatic mutations in RET associated with hereditary and sporadic forms, respectively. The most common somatic form mutation is M918T (exon 16) and a variety of other mutations effecting exons 10, 11 and 15 have been described. The prognostic significance of these mutations have been hotly debated in the field, however, data suggests that some RET mutation may confer drug resistance. Highly selective and well-tolerated RET inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), have been FDA approved recently for the treatment of RET fusion-positive non-small-cell lung cancer, RET fusion-positive thyroid cancer and RET-mutant medullary thyroid cancer.

From intOGen — cancer-driver classification: activating (oncogene-like) across 6 cancer types — ANGS, MEL, NSCLC, PGNG, SOFT_TISSUE, WDTC.

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for RET: 4,413 ClinVar records (172 pathogenic / likely pathogenic); 12 CIViC cancer variants; 14 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

4,413 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	104
Likely pathogenic	68
Uncertain significance	2082
Likely benign	1366
Benign	97

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 172 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
13951	NM_020975.6(RET):c.2671T>G (p.Ser891Ala)	Pathogenic	criteria provided, multiple submitters, no conflicts	29
38612	NM_020975.6(RET):c.2370G>T (p.Leu790Phe)	Pathogenic	criteria provided, multiple submitters, no conflicts	28
13933	NM_020975.6(RET):c.1826G>A (p.Cys609Tyr)	Pathogenic	criteria provided, multiple submitters, no conflicts	23
13946	NM_020975.6(RET):c.2410G>T (p.Val804Leu)	Pathogenic	criteria provided, multiple submitters, no conflicts	20
13914	NM_020975.6(RET):c.1853G>C (p.Cys618Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	18
13928	NM_020975.6(RET):c.1859G>T (p.Cys620Phe)	Pathogenic	criteria provided, multiple submitters, no conflicts	18
13915	NM_020975.6(RET):c.1858T>C (p.Cys620Arg)	Pathogenic	criteria provided, multiple submitters, no conflicts	16
24898	NM_020975.6(RET):c.1832G>A (p.Cys611Tyr)	Pathogenic	criteria provided, multiple submitters, no conflicts	16
13905	NM_020975.6(RET):c.1852T>G (p.Cys618Gly)	Pathogenic	criteria provided, multiple submitters, no conflicts	15
13908	NM_020975.6(RET):c.1900T>G (p.Cys634Gly)	Pathogenic	criteria provided, multiple submitters, no conflicts	12
13916	NM_020975.6(RET):c.1859G>A (p.Cys620Tyr)	Pathogenic	criteria provided, multiple submitters, no conflicts	11
13911	NM_020975.6(RET):c.1901G>T (p.Cys634Phe)	Pathogenic	criteria provided, multiple submitters, no conflicts	10
13943	NM_020975.6(RET):c.1859G>C (p.Cys620Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	10
38601	NM_020975.6(RET):c.1852T>A (p.Cys618Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	10
13918	NM_020975.6(RET):c.1902C>G (p.Cys634Trp)	Pathogenic	criteria provided, multiple submitters, no conflicts	9

Per-variant reference — Sugi Variant

Explore RET’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 26 predictions of 1,889):

Position(s)	Effect	Δscore	Sites
10:43077332	donor_loss	1.0000
10:43100710	donor_gain	1.0000
10:43106543	donor_gain	1.0000
10:43109029–43109030	acceptor_loss	1.0000	6
10:43109231–43109232	donor_loss	1.0000	5
10:43111205	acceptor_loss	1.0000	2
10:43111426	donor_gain	1.0000
10:43111466–43111467	donor_loss	1.0000	3
10:43112225–43112226	donor_loss	1.0000	5
10:43112846	acceptor_gain	1.0000

AlphaMissense

2,044 missense substitutions predicted likely pathogenic (of 7,243 scored), across 518 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M984	9	0.892	0.989
M862	9	0.888	0.979
N879	8	0.987	0.996
D874	8	0.986	0.997
D892	8	0.984	0.995
F893	8	0.972	0.995
F998	8	0.970	0.995
F735	8	0.954	0.999
D584	8	0.949	0.976
D933	8	0.948	0.970
H872	8	0.942	0.976
F937	8	0.941	0.995
F961	8	0.930	0.993
F924	8	0.924	0.990
D300	8	0.922	0.942
D264	8	0.917	0.972
F854	8	0.912	0.990
F329	8	0.904	0.984
D378	8	0.903	0.944
D302	8	0.899	0.948

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Breast Invasive Carcinoma)

Disease associations

OMIM: gene MIM:164761 | disease phenotypes: MIM:171400, MIM:142623, MIM:155240, MIM:162300, MIM:171300, MIM:209880, MIM:187500, MIM:114550, MIM:131100, MIM:167000, MIM:148300, MIM:191830, MIM:114500

GenCC curated gene-disease

10 curated gene-disease records:

Disease	Classification	Inheritance	Records
multiple endocrine neoplasia type 2B	Definitive	Autosomal dominant	4
multiple endocrine neoplasia type 2A	Definitive	Autosomal dominant	3
familial medullary thyroid carcinoma	Definitive	Autosomal dominant	2
pheochromocytoma	Definitive	Autosomal dominant
Hirschsprung disease, susceptibility to, 1	Strong	Autosomal dominant
bilateral renal agenesis	Supportive	Autosomal recessive
Hirschsprung disease	Supportive	Autosomal dominant
renal agenesis, unilateral	Supportive	Autosomal dominant
Haddad syndrome	Supportive	Autosomal dominant
renal agenesis	Limited	Autosomal recessive

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

2 validity classifications:

Disease	Classification	Inheritance
multiple endocrine neoplasia type 2B	Definitive	AD
multiple endocrine neoplasia type 2A	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (25 panels, 24 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

25 panels:

Panel	Rating
Additional findings health related	green
Additional findings health related - adults	green
Additional findings health related - children	green
Adult solid tumours cancer susceptibility	green
Adult solid tumours for rare disease	green
CAKUT	green
Childhood solid tumours	green
Childhood solid tumours cancer susceptibility	green
DDG2P	green
Endocrine neoplasia	green
Familial Hirschsprung Disease	green
Familial hyperparathyroidism or Hypocalciuric hypercalcaemia	green
Fetal anomalies	green
Gastrointestinal neuromuscular disorders	green
Inherited phaeochromocytoma and paraganglioma	green
Inherited phaeochromocytoma and paraganglioma excluding NF1	green
Multiple endocrine neoplasia type 2	green
Multiple endocrine tumours	green
Neuroendocrine cancer pertinent cancer susceptibility	green
Paediatric disorders	green
Paediatric pseudo-obstruction syndrome	green
Thyroid cancer pertinent cancer susceptibility	green
Unexplained young onset end-stage renal disease	green
Unexplained young onset end-stage renal disease - additional genes	green
Gastrointestinal epithelial barrier disorders	amber

Mondo (26): multiple endocrine neoplasia type 2 (MONDO:0019003), multiple endocrine neoplasia type 2A (MONDO:0008234), hereditary neoplastic syndrome (MONDO:0015356), Hirschsprung disease, susceptibility to, 1 (MONDO:0007723), familial medullary thyroid carcinoma (MONDO:0007958), multiple endocrine neoplasia type 2B (MONDO:0008082), pheochromocytoma (MONDO:0008233), central hypoventilation syndrome, congenital (MONDO:0800031), Hirschsprung disease (MONDO:0018309), thyroid gland carcinoma (MONDO:0015075), constipation disorder (MONDO:0002203), gingival overgrowth (MONDO:0002507), hypothyroidism (MONDO:0005420), tetralogy of fallot (MONDO:0008542), medullary thyroid gland carcinoma (MONDO:0015277), hepatocellular carcinoma (MONDO:0007256), multiple endocrine neoplasia (MONDO:0017169), ovarian cancer (MONDO:0008170), keratoconus 1 (MONDO:0007851), renal hypodysplasia/aplasia 1 (MONDO:0024519), sensorineural hearing loss disorder (MONDO:0020678), colorectal cancer (MONDO:0005575), bilateral renal agenesis (MONDO:0015986), renal agenesis, unilateral (MONDO:0019636), Haddad syndrome (MONDO:0020493), renal agenesis (MONDO:0018470)

Orphanet (17): Multiple endocrine neoplasia type 2 (Orphanet:653), Inherited cancer-predisposing syndrome (Orphanet:140162), Multiple endocrine neoplasia type 2A (Orphanet:247698), Multiple endocrine neoplasia type 2B (Orphanet:247709), Hereditary pheochromocytoma-paraganglioma (Orphanet:29072), Hirschsprung disease (Orphanet:388), Congenital central hypoventilation syndrome (Orphanet:661), Isolated familial medullary thyroid carcinoma (Orphanet:99361), Haddad syndrome (Orphanet:99803), Rare thyroid carcinoma (Orphanet:100088), Medullary thyroid carcinoma (Orphanet:1332), Tetralogy of Fallot (Orphanet:3303), Hepatocellular carcinoma (Orphanet:88673), Multiple endocrine neoplasia (Orphanet:276161), Rare ovarian cancer (Orphanet:213500), Renal agenesis (Orphanet:411709), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

showing 60 of 143 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000104	Renal agenesis
HP:0000175	Cleft palate
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000457	Depressed nasal ridge
HP:0000486	Strabismus
HP:0000519	Developmental cataract
HP:0000526	Aniridia
HP:0000574	Thick eyebrow
HP:0000740	Episodic paroxysmal anxiety
HP:0000767	Pectus excavatum
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000843	Hyperparathyroidism
HP:0000875	Episodic hypertension
HP:0000957	Cafe-au-lait spot
HP:0000975	Hyperhidrosis
HP:0000980	Pallor
HP:0001028	Hemangioma
HP:0001069	Episodic hyperhidrosis
HP:0001095	Hypertensive retinopathy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001278	Orthostatic hypotension
HP:0001279	Syncope
HP:0001290	Generalized hypotonia
HP:0001293	Cranial nerve compression
HP:0001337	Tremor
HP:0001342	Cerebral hemorrhage
HP:0001382	Joint hypermobility
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001518	Small for gestational age
HP:0001519	Disproportionate tall stature
HP:0001522	Death in infancy
HP:0001531	Failure to thrive in infancy
HP:0001558	Decreased fetal movement
HP:0001561	Polyhydramnios
HP:0001562	Oligohydramnios
HP:0001563	Fetal polyuria
HP:0001605	Vocal cord paralysis
HP:0001618	Dysphonia
HP:0001635	Congestive heart failure
HP:0001638	Cardiomyopathy
HP:0001649	Tachycardia
HP:0001761	Pes cavus
HP:0001824	Weight loss
HP:0001920	Renal artery stenosis

GWAS associations

14 associations:

Study	Trait	p-value
GCST005289_4	Hirschsprung disease	2e-101
GCST006585_1521	Blood protein levels	4e-56
GCST003764_3	Hirschsprung disease	4e-43
GCST003764_1	Hirschsprung disease	1e-28
GCST006271_1	Hirschsprung disease	3e-21
GCST002658_5	Hirschsprung disease	6e-19
GCST000334_2	Hirschsprung disease	4e-18
GCST005289_5	Hirschsprung disease	3e-15
GCST003764_7	Hirschsprung disease	4e-14
GCST005289_3	Hirschsprung disease	5e-10
GCST009405_2	Smoking behaviour (cigarettes smoked per day)	4e-8
GCST009407_2	Smoking behaviour (cigarettes smoked per day)	3e-7
GCST005289_7	Hirschsprung disease	6e-7
GCST003465_23	Cannabis dependence symptom count	1e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0008457	cannabis dependence measurement
EFO:0006525	cigarettes per day measurement

MeSH disease descriptors

14 disease descriptors:

Descriptor	Name	Tree numbers
D006528	Carcinoma, Hepatocellular	C04.557.470.200.025.255; C04.588.274.623.160; C06.301.623.160; C06.552.697.160
D003248	Constipation	C23.888.821.150
D019214	Gingival Overgrowth	C07.465.714.258.428
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D007037	Hypothyroidism	C19.874.482
D009377	Multiple Endocrine Neoplasia	C04.588.322.400; C04.651.600; C04.700.630; C16.320.700.630; C19.344.400
D018813	Multiple Endocrine Neoplasia Type 2a	C04.588.322.400.505; C04.651.600.505; C04.700.630.505; C16.320.700.630.505; C19.344.400.505
D018814	Multiple Endocrine Neoplasia Type 2b	C04.588.322.400.510; C04.651.600.510; C04.700.630.510; C16.320.700.630.510; C19.344.400.510
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D010673	Pheochromocytoma	C04.557.465.625.650.700.725; C04.557.580.625.650.700.725
D013771	Tetralogy of Fallot	C14.240.400.849; C14.280.400.849; C16.131.240.400.849
C536911	Familial medullary thyroid carcinoma *(supp.)*
C563649	Keratoconus 1 *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (7): CHEMBL2041 (SINGLE PROTEIN), CHEMBL3430877 (CHIMERIC PROTEIN), CHEMBL3430888 (CHIMERIC PROTEIN), CHEMBL3430904 (CHIMERIC PROTEIN), CHEMBL4523602 (CHIMERIC PROTEIN), CHEMBL6195572 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195575 (PROTEIN-PROTEIN INTERACTION)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the RET protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

14 curated-mechanism drugs:

Drug	Modality	Max phase
ALECTINIB HYDROCHLORIDE	Small molecule	4
PRALSETINIB	Small molecule	4
QUIZARTINIB	Small molecule	4
REGORAFENIB	Small molecule	4
SELPERCATINIB	Small molecule	4
SORAFENIB TOSYLATE	Small molecule	4
SUNITINIB	Small molecule	4
VANDETANIB	Small molecule	4
LESTAURTINIB	Small molecule	3
MOTESANIB	Small molecule	3
BOS-589	Unknown	2
CEP-32496	Small molecule	2
AST-487	Small molecule	1
CEP-2563 DIHYDROCHLORIDE	Small molecule	1

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 401,172 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

showing 60 of 135 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1738797	ALECTINIB	4	7,111
CHEMBL4582651	PRALSETINIB	4	1,544
CHEMBL576982	QUIZARTINIB	4	4,647
CHEMBL1946170	REGORAFENIB	4	13,318
CHEMBL4559134	SELPERCATINIB	4	1,524
CHEMBL1336	SORAFENIB	4	87,476
CHEMBL535	SUNITINIB	4	80,232
CHEMBL24828	VANDETANIB	4	43,290
CHEMBL1173655	AFATINIB	4	15,878
CHEMBL629	AMITRIPTYLINE	4	53,007
CHEMBL1289926	AXITINIB	4	16,510
CHEMBL2105759	BARICITINIB	4	7,117
CHEMBL288441	BOSUTINIB	4	12,869
CHEMBL3545311	BRIGATINIB	4	5,988
CHEMBL2105717	CABOZANTINIB	4	11,799
CHEMBL2325741	CAPIVASERTIB	4	2,281
CHEMBL2403108	CERITINIB	4	9,002
CHEMBL601719	CRIZOTINIB	4	15,133
CHEMBL669	CYCLOBENZAPRINE	4	11,772
CHEMBL5416410	DASATINIB	4	674
CHEMBL1421	DASATINIB ANHYDROUS	4
CHEMBL1983268	ENTRECTINIB	4
CHEMBL553	ERLOTINIB	4
CHEMBL1287853	FEDRATINIB	4
CHEMBL2103830	FOSTAMATINIB	4
CHEMBL939	GEFITINIB	4
CHEMBL3301622	GILTERITINIB	4
CHEMBL1873475	IBRUTINIB	4
CHEMBL1852688	INFIGRATINIB	4
CHEMBL1834657	INFIGRATINIB PHOSPHATE	4
CHEMBL554	LAPATINIB	4
CHEMBL1289601	LENVATINIB	4
CHEMBL608533	MIDOSTAURIN	4
CHEMBL255863	NILOTINIB	4
CHEMBL502835	NINTEDANIB	4
CHEMBL445	NORTRIPTYLINE	4
CHEMBL189963	PALBOCICLIB	4
CHEMBL477772	PAZOPANIB	4
CHEMBL1171837	PONATINIB	4
CHEMBL1789941	RUXOLITINIB	4
CHEMBL1289494	TIVOZANIB	4
CHEMBL221959	TOFACITINIB	4
CHEMBL2103743	TOFACITINIB CITRATE	4
CHEMBL3622821	UPADACITINIB	4
CHEMBL1229517	VEMURAFENIB	4
CHEMBL603469	LESTAURTINIB	3
CHEMBL572881	MOTESANIB	3
CHEMBL483158	ALISERTIB	3
CHEMBL627	AMITRIPTYLINOXIDE	3
CHEMBL415049	BARASERTIB	3
CHEMBL377300	BRIVANIB	3
CHEMBL270995	BRIVANIB ALANINATE	3
CHEMBL31965	CANERTINIB	3
CHEMBL491473	CEDIRANIB	3
CHEMBL2105728	CRENOLANIB	3
CHEMBL3137331	DEFACTINIB	3
CHEMBL522892	DOVITINIB	3
CHEMBL223360	LINIFANIB	3
CHEMBL274654	ORANTINIB	3
CHEMBL3545154	POZIOTINIB	3

Clinical evidence (CIViC)

Drug × variant × indication, from 35 curated evidence items; also 7 oncogenic, 3 predisposing, 3 prognostic, 1 functional, 1 diagnostic. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

29 predictive associations by evidence level:

Variant	Therapy	Indication	Effect	Level	CIViC
RET Mutation	Selpercatinib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC A	EID12157 +2
RET Fusion OR RET Mutation	Selpercatinib	Solid Tumor	Sensitivity/Response	CIViC A	EID12056 +1
RET Fusion OR RET Mutation	Pralsetinib	Thyroid Cancer	Sensitivity/Response	CIViC A	EID11267
RET M918T	Selpercatinib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC A	EID12598
RET E632_L633del	Selpercatinib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC B	EID11875 +2
RET M918T	Sorafenib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC B	EID1365
RET M918T	Cabozantinib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC B	EID7710
RET Mutation	Cabozantinib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC B	EID8984
RET V804M	Selpercatinib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC C	EID6951 +1
RET M918T AND RET V804M	Selpercatinib	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC C	EID6950
RET Overexpression	Sunitinib	Papillary Adenocarcinoma	Sensitivity/Response	CIViC C	EID1518
KIF5B::RET Fusion AND ( RET G810C OR RET G810S OR RET G810R )	Selpercatinib	Lung Non-small Cell Carcinoma	Resistance	CIViC C	EID8195
RET M918T AND RET G810S	Selpercatinib	Medullary Thyroid Carcinoma	Resistance	CIViC C	EID8196
RET C618R	Selpercatinib	Cancer	Sensitivity/Response	CIViC D	EID11877
RET C634W	Regorafenib Anhydrous	Gastrointestinal Stromal Tumor	Sensitivity/Response	CIViC D	EID3695
RET E632_L633del	Selpercatinib	Cancer	Sensitivity/Response	CIViC D	EID12712
RET E632_L633del	Pralsetinib	Cancer	Sensitivity/Response	CIViC D	EID12815
RET M918T	Selpercatinib + Pralsetinib	Cancer	Sensitivity/Response	CIViC D	EID11867
RET M918T	Selpercatinib	Cancer	Sensitivity/Response	CIViC D	EID11876
RET M918T	JAK2 Inhibitor AZD1480	Medullary Thyroid Carcinoma	Sensitivity/Response	CIViC D	EID77
RET Mutation	NVP-AST487 + Sapanisertib	Thyroid Gland Carcinoma	Sensitivity/Response	CIViC D	EID4854
RET Overexpression	Vandetanib	Estrogen Receptor-negative Breast Cancer	Sensitivity/Response	CIViC D	EID2992
RET Overexpression	Vandetanib	Breast Cancer	Sensitivity/Response	CIViC D	EID740
RET C634W	Axitinib	Medullary Thyroid Carcinoma	Resistance	CIViC D	EID3694
RET C634W	Motesanib	Medullary Thyroid Carcinoma	Resistance	CIViC D	EID75
RET E632_L633del	Selpercatinib + Pralsetinib	Cancer	Resistance	CIViC D	EID12715
RET M918T	Axitinib	Medullary Thyroid Carcinoma	Resistance	CIViC D	EID3696
RET M918T	Motesanib	Medullary Thyroid Carcinoma	Resistance	CIViC D	EID76
RET V804M	Dasatinib	Chronic Myeloid Leukemia	Resistance	CIViC D	EID7516

CIViC column: a representative evidence item (EID); +N = additional CIViC items supporting the same association.

Clinical-actionability assertions (CIViC AMP/ASCO/CAP)

Curated AMP/ASCO/CAP tier assertions — the clinical-actionability classification (Tier I highest) for this gene’s variants, distilling the CIViC evidence above into a tiered call.

5 CIViC assertions:

Molecular profile	Disease	Therapy	Type	AMP tier	Significance
RET M918T	Medullary Thyroid Carcinoma	Selpercatinib †	Predictive	Tier I - Level A	Sensitivity/Response
RET E632_L633del	Medullary Thyroid Carcinoma	Selpercatinib †	Predictive	Tier I - Level A	Sensitivity/Response
RET Mutation	Medullary Thyroid Carcinoma	Selpercatinib †	Predictive	Tier I - Level A	Sensitivity/Response
RET M918T	Medullary Thyroid Carcinoma		Oncogenic		Likely Oncogenic
RET E632_L633del	Medullary Thyroid Carcinoma		Oncogenic		Oncogenic

† an FDA-approved companion diagnostic exists for this assertion.

CIViC curated variants (12)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

C634W (missense variant), M918T (missense variant), C609Y (missense variant), Mutation, C634R, V804M, G810C, G810S, E632_L633del (deletion), C618R, G810R, Overexpression.

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Type XIV RTKs: RET

Most potent curated ligand interactions (28 total), top 25:

Ligand	Action	Affinity	Parameter
APS03118	Inhibition	10.02	pIC50
vepafestinib	Inhibition	9.7	pIC50
compound 8h [PMID: 21561767]	Inhibition	9.7	pIC50
resencatinib	Inhibition	9.47	pIC50
pralsetinib	Inhibition	9.4	pIC50
soxataltinib	Inhibition	9.4	pIC50
compound 1 [PMID: 34917254]	Inhibition	9.17	pIC50
WF-47-JS03	Inhibition	9.0	pIC50
sunitinib	Inhibition	8.8	pIC50
gilteritinib	Inhibition	8.77	pIC50
zeteletinib	Inhibition	8.34	pIC50
tamatinib	Inhibition	8.3	pIC50
CEP-11981	Inhibition	8.3	pIC50
ponatinib	Inhibition	8.2	pIC50
lunbotinib	Inhibition	8.18	pIC50
KBP-7018	Inhibition	8.12	pIC50
quizartinib	Inhibition	8.0	pKd
cabozantinib	Inhibition	7.96	pIC50
sorafenib	Inhibition	7.9	pIC50
rivoceranib	Inhibition	7.89	pIC50
selpercatinib	Inhibition	7.85	pIC50
compound 1d [PMID: 21493067]	Inhibition	7.72	pIC50
RG-1530	Inhibition	7.66	pKd
tafetinib	Inhibition	7.17	pIC50
vandetanib	Inhibition	7.0	pIC50

Binding affinities (BindingDB)

4315 measured of 4901 human assays (4929 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-amino-6-[2-(1-hydroxycyclopentyl)ethynyl]-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.04 nM	US-11014930: Fused pyrimidine compound or salt thereof
3-[2-(Imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide	EC50	0.05 nM
6-(1-methyl-1Hpyrazol-4-yl)-4-(6-(6-(4-(methylthio)benzyl)-3,6-diazabicyclo[3.1.1] heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.066 nM	US-12583855: RET selective inhibitor, preparation method therefor and use thereof
4-amino-6-(3-hydroxy-3-methylbut-1-ynyl)-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.07 nM	US-11014930: Fused pyrimidine compound or salt thereof
4-amino-7-(1-methylcyclopropyl)-N-(5-methylpyrazolidin-3-yl)-6-(2-pyridin-3-ylethynyl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.09 nM	US-11014930: Fused pyrimidine compound or salt thereof
4-amino-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)-6-(3-morpholin-4-ylprop-1-ynyl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.1 nM	US-11014930: Fused pyrimidine compound or salt thereof
CHEMBL4218013	IC50	0.1 nM
CHEMBL5593687	IC50	0.1 nM
CHEMBL5619652	IC50	0.1 nM
7-chloro-3-(5-cyclopropyl-4-pyridin-2-yl-1,2-oxazol-3-yl)-1-propan-2-ylpyrazolo[4,5-c]pyridin-4-amine	IC50	0.1 nM	US-11472802: Substituted pyrazolyl[4,3-c]pyridine compounds as RET kinase inhibitors
(2S)-2-(((4-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.3.1]heptan-3-yl)pyridin-3-yl)-1H-pyrazolo[3’,4’:3,4]pyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)morpholine	IC50	0.1 nM	US-12338253: Nitrogen-containing polycyclic fused ring compound, pharmaceutical composition thereof, preparation method therefor and use thereof
(3-(5-(6-(2-fluoroethoxy)-1H-pyrazolo[3’,4’:3,4]pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.3.1]heptan-6-yl)(6-methoxypyridin-3-yl)methanone	IC50	0.1 nM	US-12338253: Nitrogen-containing polycyclic fused ring compound, pharmaceutical composition thereof, preparation method therefor and use thereof
4-(6-(6-(4-nitrobenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-(difluoromethyl)-1Hpyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.12 nM	US-12583855: RET selective inhibitor, preparation method therefor and use thereof
6-(1-difluoromethyl-1Hpyrazol-4-yl)-4-(6-(6-(4-(methylthio)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.136 nM	US-12583855: RET selective inhibitor, preparation method therefor and use thereof
4-amino-6-bromo-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.14 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-6-bromo-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.14 nM	US-11014930: Fused pyrimidine compound or salt thereof
4-amino-N-(5-bromo-1H-pyrazol-3-yl)-1-tert-butylpyrazolo[3,4-d]pyrimidine-3-carboxamide	IC50	0.15 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-(1-fluoro-2-methylpropan-2-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.15 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-(1-fluoro-2-methylpropan-2-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.15 nM	US-11014930: Fused pyrimidine compound or salt thereof
4-amino-N-(5-bromo-1H-pyrazol-3-yl)-7-(1-methylcyclopropyl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.15 nM	US-11014930: Fused pyrimidine compound or salt thereof
4-amino-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)-6-[2-(1-methylpyrazol-4-yl)ethynyl]pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.15 nM	US-11014930: Fused pyrimidine compound or salt thereof
4-amino-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)-6-[2-(oxan-4-yl)ethynyl]pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.15 nM	US-11014930: Fused pyrimidine compound or salt thereof
6-(3,3-difluoroazetidin-1-yl)-4-[6-[6-[(5-methoxy-2-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.159 nM	US-12583855: RET selective inhibitor, preparation method therefor and use thereof
4-amino-1-(2-cyclopropylpropan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide	IC50	0.16 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-(6-(6-((6-methoxypyridin-3-yl)methyl-d2)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.16 nM	US-12129266: Substituted pyrazolo[1,5-a]pyridine compound, composition containing the same and use thereof
4-[6-[6-[3-(5-methoxy-3-pyridinyl)prop-2-ynyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.16 nM	US-12209085
4-amino-1-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide	IC50	0.17 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-7-(1-methylcyclopropyl)-6-[2-(3-methylimidazol-4-yl)ethynyl]-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.17 nM	US-11014930: Fused pyrimidine compound or salt thereof
4-(6-(6-((6-(methoxy-d3)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.17 nM	US-12129266: Substituted pyrazolo[1,5-a]pyridine compound, composition containing the same and use thereof
6-(1-methylpyrazol-4-yl)-4-[6-[6-[(6-methylsulfanyl-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.181 nM	US-12583855: RET selective inhibitor, preparation method therefor and use thereof
CHEMBL4218563	IC50	0.2 nM
CHEMBL6133093	IC50	0.2 nM
4-[6-[3-[(6-ethynyl-3-pyridinyl)oxy]azetidin-1-yl]-3-pyridinyl]-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.2 nM	US-12209085
2-[2-fluoro-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl]-N-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]acetamide	IC50	0.2 nM	US-12365685: Substituted fused aromatic ring derivative, composition and use thereof
6-(1-methylpyrazol-4-yl)-4-[6-[4-[(2-methylsulfonylphenyl)methyl]piperazin-1-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.2 nM	US-12583855: RET selective inhibitor, preparation method therefor and use thereof
CHEMBL6144946	IC50	0.203 nM
6-(1-methylpyrazol-4-yl)-4-[6-[4-[(3-methylsulfonylphenyl)methyl]piperazin-1-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.206 nM	US-12583855: RET selective inhibitor, preparation method therefor and use thereof
4-amino-1-tert-butyl-N-(5-methyl-1H-pyrazol-3-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide	IC50	0.21 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.21 nM	US-12129266: Substituted pyrazolo[1,5-a]pyridine compound, composition containing the same and use thereof
4-[6-[6-[3-(3-fluoro-2-pyridinyl)prop-2-ynyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.21 nM	US-12209085
2-[6-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-3-yl]-3-pyridinyl]-N-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]acetamide	IC50	0.21 nM	US-12365685: Substituted fused aromatic ring derivative, composition and use thereof
CHEMBL6160666	IC50	0.215 nM
4-[6-[6-[(3-ethynyl-4-fluorophenyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.22 nM	US-12209085
CHEMBL6166173	IC50	0.227 nM
5-[(4-hydroxycyclohexyl)amino]-3-[4-(4-methylpiperazin-1-yl)anilino]-6-propan-2-ylpyrazine-2-carboxamide	IC50	0.23 nM	US-8969336: Diamino heterocyclic carboxamide compound
4-amino-1-[1-(fluoromethyl)cyclopropyl]-N-(5-methyl-1H-pyrazol-3-yl)pyrazolo[3,4-d]pyrimidine-3-carboxamide	IC50	0.23 nM	US-10233189: Fused pyrimidine compound or salt thereof
4-amino-7-[1-(fluoromethyl)cyclopropyl]-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide	IC50	0.23 nM	US-10787457: Fused pyrimidine compound or salt thereof
4-(6-(6-((6-methoxypyridin-3-yl)methyl-d2)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.23 nM	US-12129266: Substituted pyrazolo[1,5-a]pyridine compound, composition containing the same and use thereof
2-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]-N-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]acetamide	IC50	0.23 nM	US-12365685: Substituted fused aromatic ring derivative, composition and use thereof
6-(1-methylpyrazol-4-yl)-4-[6-[6-[(4-methylsulfonylphenyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile	IC50	0.236 nM	US-12583855: RET selective inhibitor, preparation method therefor and use thereof

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 49 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.77	IC50	0.017	nM	CHEMBL5962713
10.40	IC50	0.04	nM	CHEMBL4067871
10.40	IC50	0.04	nM	CHEMBL5944764
10.15	IC50	0.07	nM	CHEMBL5916213
10.05	IC50	0.09	nM	CHEMBL5838635
10.00	IC50	0.1	nM	CHEMBL4218013
10.00	IC50	0.1	nM	CHEMBL5619652
10.00	IC50	0.1	nM	CHEMBL5915060
10.00	IC50	0.1	nM	CHEMBL5913548
10.00	IC50	0.1	nM	CHEMBL6034872
10.00	IC50	0.1	nM	CHEMBL5936500
10.00	IC50	0.1	nM	CHEMBL5902423
10.00	IC50	0.1	nM	CHEMBL6035624
10.00	IC50	0.1	nM	CHEMBL5786997
10.00	IC50	0.1	nM	SELPERCATINIB
9.89	IC50	0.13	nM	VANDETANIB
9.85	IC50	0.14	nM	CHEMBL5807109
9.82	IC50	0.15	nM	CHEMBL5909127
9.82	IC50	0.15	nM	CHEMBL5876102
9.82	IC50	0.15	nM	CHEMBL5787119
9.82	IC50	0.15	nM	CHEMBL5753786
9.82	IC50	0.15	nM	CHEMBL5747405
9.82	IC50	0.15	nM	CHEMBL5895474
9.80	IC50	0.16	nM	CHEMBL5949802
9.80	IC50	0.16	nM	CHEMBL5992123
9.77	IC50	0.17	nM	CHEMBL5757468
9.77	IC50	0.17	nM	CHEMBL5747090
9.77	IC50	0.17	nM	CHEMBL5982797
9.75	IC50	0.177	nM	SELPERCATINIB
9.70	IC50	0.2	nM	CHEMBL4062877
9.70	IC50	0.2	nM	CHEMBL4218563
9.70	IC50	0.2	nM	CHEMBL5806749
9.70	IC50	0.2	nM	CHEMBL5799517
9.70	IC50	0.2	nM	CHEMBL5824514
9.70	IC50	0.2	nM	CHEMBL5966131
9.70	IC50	0.2	nM	CHEMBL5823521
9.70	IC50	0.2	nM	CHEMBL5838948
9.70	IC50	0.2	nM	CHEMBL5907426
9.70	IC50	0.2	nM	CHEMBL5977183
9.70	IC50	0.2	nM	CHEMBL5887763
9.70	IC50	0.2	nM	CHEMBL5747869
9.70	IC50	0.2	nM	CHEMBL5856917
9.70	IC50	0.2	nM	CHEMBL5783077
9.70	IC50	0.2	nM	CHEMBL5895415
9.70	IC50	0.2	nM	CHEMBL6036577
9.70	IC50	0.2	nM	CHEMBL5847789
9.70	IC50	0.2	nM	CHEMBL5891634
9.70	IC50	0.2	nM	CHEMBL5944502
9.70	IC50	0.2	nM	CHEMBL5796281

PubChem BioAssay actives

1883 with measured affinity, of 5349 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-chloro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-isoquinolin-6-yl-2-pyridinyl]phenol	1450708: Inhibition of recombinant Ret (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	<0.0001	uM
1-[4-(5-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]-3-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]urea	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0001	uM
Selpercatinib	2255225: Inhibition of RET V804L mutant (unknown origin) by FRET-based ZLyte kinase assay	ic50	0.0001	uM
N-[1-[5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)-2-pyridinyl]-4-[[4-[7-[4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]piperazin-1-yl]heptanoyl]piperazin-1-yl]methyl]piperidin-4-yl]-2,5-difluorobenzamide	2207101: Inhibition of CCDC6-RET in human TPC1 cells assessed as reduction in phospho-RET level by AlphaLISA analysis	ic50	0.0001	uM
N-[1-[5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)-2-pyridinyl]-4-[[4-[3-[4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]piperidin-1-yl]propanoyl]piperazin-1-yl]methyl]piperidin-4-yl]-2,5-difluorobenzamide	2207101: Inhibition of CCDC6-RET in human TPC1 cells assessed as reduction in phospho-RET level by AlphaLISA analysis	ic50	0.0001	uM
4-methyl-N-[3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)phenyl]-3-[2-(6-morpholin-4-ylimidazo[1,2-b]pyridazin-3-yl)ethynyl]benzamide	2130925: Inhibition of human RET kinase-V804M mutant using RRRRRRRRRRRVYSTDYYRLFNPS as substrate in presence of [gamma33P]-ATP and 10 uM ATP by radiometric HotSpot assay	ic50	0.0001	uM
Vandetanib	1895639: Inhibition of RET (unknown origin)	ic50	0.0001	uM
4-fluoro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-(3-methyl-2H-indazol-5-yl)-2-pyridinyl]phenol	1450708: Inhibition of recombinant Ret (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0002	uM
N-[4-(2-amino-2-methylpropyl)-3-(trifluoromethyl)phenyl]-2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0002	uM
N-[1-[5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)-2-pyridinyl]-4-[[4-[2-[4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]piperazin-1-yl]spiro[3.3]heptane-6-carbonyl]piperazin-1-yl]methyl]piperidin-4-yl]-2,5-difluorobenzamide	2207101: Inhibition of CCDC6-RET in human TPC1 cells assessed as reduction in phospho-RET level by AlphaLISA analysis	ic50	0.0002	uM
N-[1-[5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)-2-pyridinyl]-4-[[4-[3-[4-[2-[(3S)-2,6-dioxopiperidin-3-yl]-3-oxo-1H-isoindol-5-yl]piperidin-1-yl]propanoyl]piperazin-1-yl]methyl]piperidin-4-yl]-2,5-difluorobenzamide	2207101: Inhibition of CCDC6-RET in human TPC1 cells assessed as reduction in phospho-RET level by AlphaLISA analysis	ic50	0.0002	uM
N-[1-[5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)-2-pyridinyl]-4-[[4-[4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]piperazin-1-yl]piperidin-1-yl]methyl]piperidin-4-yl]-2,5-difluorobenzamide	2207064: Binding affinity to GST/His-tagged recombinant human RET V804M mutant extracted from baculovirus incubated for 1 hrs by HTRF assay	ic50	0.0002	uM
6-[4-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]azetidin-3-yl]piperazin-1-yl]-4-[6-[6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile	2229018: Inhibition of RET (unknown origin) preincubated for 10 mins followed by substrate/ATP addition measured after 30 mins by HTRF assay	ic50	0.0002	uM
6-[4-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]azetidin-3-yl]methyl]piperazin-1-yl]-4-[6-[6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile	2229018: Inhibition of RET (unknown origin) preincubated for 10 mins followed by substrate/ATP addition measured after 30 mins by HTRF assay	ic50	0.0002	uM
6-[4-[8-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]octanoyl]piperazin-1-yl]-4-[6-[6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile	2229018: Inhibition of RET (unknown origin) preincubated for 10 mins followed by substrate/ATP addition measured after 30 mins by HTRF assay	ic50	0.0002	uM
2-methoxy-5-[[3-[5-[7-(1-methylpyrazol-4-yl)-1,6-naphthyridin-5-yl]-2-pyridinyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]methyl]benzonitrile	2255225: Inhibition of RET V804L mutant (unknown origin) by FRET-based ZLyte kinase assay	ic50	0.0002	uM
5-[2-[5-[[4-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-3-(trifluoromethyl)phenyl]carbamoyl]-2-methylphenyl]ethynyl]-N,1-dimethylimidazole-2-carboxamide	601224: Inhibition of human RET using KKKSPGEYVNIEFG by Hotspot assay	ic50	0.0002	uM
N-[(1S)-1-[6-(4-fluoropyrazol-1-yl)-3-pyridinyl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]cyclohexane-1-carboxamide	1895756: Inhibition of recombinant RET V804L (unknown origin) incubated for 120 mins by Perkin Elmer electrophoretic mobility shift platform method	ic50	0.0003	uM
6-(2-hydroxy-2-methylpropoxy)-4-[6-[(1S,5R)-6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile	1995913: Binding affinity to RET (unknown origin) assessed as dissociation constant in presence of ATP by FRET based Z’-Lyte assay	kd	0.0003	uM
N-[1-[5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)-2-pyridinyl]-4-[[4-[3-[4-[2-[(3R)-2,6-dioxopiperidin-3-yl]-3-oxo-1H-isoindol-5-yl]piperidin-1-yl]propanoyl]piperazin-1-yl]methyl]piperidin-4-yl]-2,5-difluorobenzamide	2207101: Inhibition of CCDC6-RET in human TPC1 cells assessed as reduction in phospho-RET level by AlphaLISA analysis	ic50	0.0003	uM
6-[4-[4-[6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]hexanoyl]piperazin-1-yl]piperidin-1-yl]-4-[6-[6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile	2229018: Inhibition of RET (unknown origin) preincubated for 10 mins followed by substrate/ATP addition measured after 30 mins by HTRF assay	ic50	0.0003	uM
6-[4-[4-[4-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]butanoyl]piperazin-1-yl]piperidin-1-yl]-4-[6-[6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile	2229018: Inhibition of RET (unknown origin) preincubated for 10 mins followed by substrate/ATP addition measured after 30 mins by HTRF assay	ic50	0.0003	uM
5-[6-[6-[(3-fluoro-4-methoxyphenyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]-7-(1-methylpyrazol-4-yl)-1,6-naphthyridine	2255225: Inhibition of RET V804L mutant (unknown origin) by FRET-based ZLyte kinase assay	ic50	0.0003	uM
Ponatinib	1435448: Inhibition of recombinant RET (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0003	uM
1-[3-(6,7-dimethoxyquinazolin-4-yl)oxyphenyl]-3-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]urea	1895750: Inhibition of CCDC6-RET (unknown origin)	ic50	0.0003	uM
5-fluoro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-(3-methyl-2H-indazol-5-yl)-2-pyridinyl]phenol	1450708: Inhibition of recombinant Ret (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0004	uM
2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]-N-[4-(2-hydroxy-2-methylpropyl)-3-(trifluoromethyl)phenyl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0004	uM
2-[(1S)-1-[6-(4-fluoropyrazol-1-yl)-3-pyridinyl]ethyl]-9-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,9-diazaspiro[5.5]undecan-1-one	1776959: Inhibition of RET wild type (unknown origin)	ic50	0.0004	uM
6-[4-[4-[5-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]pent-4-ynyl]piperazin-1-yl]piperidin-1-yl]-4-[6-[6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile	2229018: Inhibition of RET (unknown origin) preincubated for 10 mins followed by substrate/ATP addition measured after 30 mins by HTRF assay	ic50	0.0004	uM
6-[4-[4-[6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]amino]hexanoyl]piperazin-1-yl]piperidin-1-yl]-4-[6-[6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]pyrazolo[1,5-a]pyridine-3-carbonitrile	2229018: Inhibition of RET (unknown origin) preincubated for 10 mins followed by substrate/ATP addition measured after 30 mins by HTRF assay	ic50	0.0004	uM
5-[6-[6-[(6-methoxy-3-pyridinyl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]-3-pyridinyl]-7-(1-methylpyrazol-4-yl)-1,6-naphthyridine	2255225: Inhibition of RET V804L mutant (unknown origin) by FRET-based ZLyte kinase assay	ic50	0.0004	uM
5-[(6,7-dimethoxyquinazolin-4-yl)amino]-2,4-difluorophenol	1283956: Inhibition of human RET cytoplasmic domain (658 to 1114 residues) expressed in baculovirus system preincubated for 15 mins followed by substrate addition measured after 20 mins by HTRF assay	ic50	0.0004	uM
2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]-N-[4-(3-hydroxy-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0004	uM
2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]-N-[3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-5-yl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0004	uM
2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]-N-[3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0004	uM
2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]-N-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0004	uM
1-[4-[3-[4-amino-5-(2-fluoro-5-hydroxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclobutyl]piperazin-1-yl]ethanone	1774914: Inhibition of RET (658 to 1072) (unknown origin) by HTRF assay	ic50	0.0005	uM
3-[2-(6-chloroimidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-[3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)phenyl]benzamide	2130925: Inhibition of human RET kinase-V804M mutant using RRRRRRRRRRRVYSTDYYRLFNPS as substrate in presence of [gamma33P]-ATP and 10 uM ATP by radiometric HotSpot assay	ic50	0.0005	uM
4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-[6-[2-(propan-2-ylamino)ethoxy]imidazo[1,2-b]pyridazin-3-yl]ethynyl]benzamide	2130925: Inhibition of human RET kinase-V804M mutant using RRRRRRRRRRRVYSTDYYRLFNPS as substrate in presence of [gamma33P]-ATP and 10 uM ATP by radiometric HotSpot assay	ic50	0.0005	uM
4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[2-[6-(2-morpholin-4-ylethoxy)imidazo[1,2-b]pyridazin-3-yl]ethynyl]benzamide	2130925: Inhibition of human RET kinase-V804M mutant using RRRRRRRRRRRVYSTDYYRLFNPS as substrate in presence of [gamma33P]-ATP and 10 uM ATP by radiometric HotSpot assay	ic50	0.0005	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	350292: Inhibition of RET	ic50	0.0005	uM
N-[4-(2,2-dimethyl-3-methylsulfonylpropyl)-3-(trifluoromethyl)phenyl]-2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0006	uM
2-[(1S)-1-[5-(4-fluoropyrazol-1-yl)pyrazin-2-yl]ethyl]-9-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2,9-diazaspiro[5.5]undecan-1-one	1776961: Inhibition of RET M918T mutant (unknown origin)	ic50	0.0006	uM
N-[1-[5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)-2-pyridinyl]-4-[[4-[3-[4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]piperidin-1-yl]cyclobutanecarbonyl]piperazin-1-yl]methyl]piperidin-4-yl]-2,5-difluorobenzamide	2207101: Inhibition of CCDC6-RET in human TPC1 cells assessed as reduction in phospho-RET level by AlphaLISA analysis	ic50	0.0006	uM
N-[1-[5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)-2-pyridinyl]-4-[[4-[3-[4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]piperidin-1-yl]propanoyl]piperazin-1-yl]methyl]piperidin-4-yl]-3-fluoropyridine-2-carboxamide	2207064: Binding affinity to GST/His-tagged recombinant human RET V804M mutant extracted from baculovirus incubated for 1 hrs by HTRF assay	ic50	0.0006	uM
N-(5-tert-butyl-1,2-oxazol-3-yl)-2-[4-[5-(4-methylsulfonylphenyl)benzimidazol-1-yl]phenyl]acetamide	1561828: Inhibition of RET isoform 9 C634W mutant in human TT cells assessed as reduction in cell proliferation supplemented with fresh medium containing compound for every 2 to 3 days and measured during compound dosing	ic50	0.0007	uM
4-chloro-2-[5-[[(1R)-2-hydroxy-1-phenylethyl]amino]-3-(3-methyl-2H-indazol-5-yl)-2-pyridinyl]phenol	1450708: Inhibition of recombinant Ret (unknown origin) using poly (Glu,Tyr) 4:1 as substrate after 60 mins by ELISA	ic50	0.0007	uM
N-[4-(1-cyanoethyl)-3-(trifluoromethyl)phenyl]-2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]acetamide	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0007	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)-3-pyridinyl]phenyl]urea	1384880: Inhibition of human RET using cisbio TK biotin-peptide as substrate preincubated for 30 mins followed by substrate addition measured after 1 hr by HTRF assay	ic50	0.0007	uM
1-[4-[3-[4-amino-5-(4-chloro-3-hydroxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclobutyl]piperazin-1-yl]ethanone	1774914: Inhibition of RET (658 to 1072) (unknown origin) by HTRF assay	ic50	0.0007	uM

CTD chemical–gene interactions

89 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tretinoin	increases response to substance, decreases expression, increases activity, increases expression, increases phosphorylation (+1 more)	8
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	7
Estradiol	affects cotreatment, decreases expression, increases expression, decreases reaction	5
sodium arsenite	affects methylation, affects cotreatment, decreases expression, increases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
ponatinib	decreases activity	2
Resveratrol	increases expression, decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tamoxifen	affects cotreatment, increases expression, decreases expression, decreases reaction	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
Raloxifene Hydrochloride	decreases expression, affects cotreatment, increases expression	2
pralsetinib	decreases phosphorylation	1
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
lead acetate	affects cotreatment, decreases expression	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
afimoxifene	decreases reaction, increases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
chromous chloride	affects cotreatment, decreases expression	1
butyraldehyde	increases expression	1
chromic oxide	affects cotreatment, decreases expression	1
benzo(e)pyrene	increases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	increases expression, affects cotreatment	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
indeno(1,2,3-cd)pyrene	decreases expression	1

ChEMBL screening assays

1586 unique, capped per target: 1573 binding, 10 functional, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1005547	Binding	Inhibition of Tel-fused RET kinase-mediated mouse BaF3 cell proliferation	Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK. — *Proc Natl Acad Sci U S A*
CHEMBL1963706	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: RET	PubChem BioAssay data set
CHEMBL4313074	ADMET	Inhibition of human Ret at 1000 nM using poly (Glu, Tyr)4:1 as substrate measured after 60 mins by ELISA relative to control	Discovery and Development of a Series of Pyrazolo[3,4-d]pyridazinone Compounds as the Novel Covalent Fibroblast Growth Factor Receptor Inhibitors by the Rational Drug Design. — *J Med Chem*

Cellosaurus cell lines

60 cell lines: 40 cancer cell line, 6 induced pluripotent stem cell, 5 transformed cell line, 5 factor-dependent cell line, 3 embryonic stem cell, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1150	CTV-1	Cancer cell line	Male
CVCL_1326	Karpas-45	Cancer cell line	Male
CVCL_1373	LC-2/ad	Cancer cell line	Female
CVCL_1621	OCUB-M	Cancer cell line	Female
CVCL_1774	TT	Cancer cell line	Female
CVCL_2022	DND-41	Cancer cell line	Male
CVCL_4W01	BHP2-7 Pazopanib selected	Cancer cell line	Female
CVCL_6278	BHP 10-3	Cancer cell line	Female
CVCL_6283	BHP 2-7	Cancer cell line	Female
CVCL_6285	BHP 7-13	Cancer cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 232 trials:

NCT	Phase	Status	Title
NCT02343562	Phase 4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	Phase 4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT01379898	Phase 4	COMPLETED	Phenoxybenzamine Versus Doxazosin in PCC Patients
NCT01959711	Phase 4	COMPLETED	Randomized Clinical Trial of Posterior Retroperitoneoscopic Adrenalectomy Versus Lateral Laparoscopic Adrenalectomy
NCT05702944	Phase 4	RECRUITING	The Effect and Safety of Omitting Preoperative Alpha-adrenergic Blockade for Normotensive Pheochromocytoma
NCT04904081	Phase 3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT03660176	Phase 3	NOT_YET_RECRUITING	Effects of Butyrate Enemas on Postoperative Intestinal Motility Disorders in Hirschsprung’s Disease
NCT01373736	Phase 3	UNKNOWN	123I-MIBG Scintigraphy in Patients Being Evaluated for Neuroendocrine Tumors
NCT07383246	Phase 3	RECRUITING	CTR-FAPI-guided Precision Surgery for Newly Diagnosed MTC
NCT00002641	Phase 3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002764	Phase 3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00126412	Phase 3	COMPLETED	Meta-Iodobenzylguanidine (123I mIBG) Scintigraphy in Patients Being Evaluated for Phaeochromocytoma or Neuroblastoma
NCT03176693	Phase 3	COMPLETED	Preoperative Alpha Blockade for Pheochromocytoma
NCT00390325	Phase 2	COMPLETED	Sorafenib Tosylate in Treating Patients With Metastatic, Locally Advanced, or Recurrent Medullary Thyroid Cancer
NCT00630838	Phase 2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT01736878	Phase 2	WITHDRAWN	Efficacy and Safety Study of Sorafenib to Treat Advanced Medullary Thyroid Carcinoma
NCT04787328	Phase 2	UNKNOWN	A Study of HA121-28 Tablets in Patients With Medullary Thyroid Carcinoma (MTC)
NCT06121271	Phase 2	NOT_YET_RECRUITING	Trial of Lu-177 DOTATATE (Lutathera®) in Unlicensed Indications
NCT00002608	Phase 2	COMPLETED	Combination Chemotherapy and Tamoxifen in Treating Patients With Solid Tumors
NCT00028106	Phase 2	COMPLETED	131MIBG to Treat Malignant Pheochromocytoma
NCT00107289	Phase 2	RECRUITING	Iodine I 131 Metaiodobenzylguanidine in Treating Patients With Recurrent, Progressive, or Refractory Neuroblastoma or Malignant Pheochromocytoma or Paraganglioma
NCT00466856	Phase 2	TERMINATED	Internal Radiation Therapy in Treating Patients With Liver Metastases From Neuroendocrine Tumors
NCT00843037	Phase 2	COMPLETED	Study Of Sunitinib In Patients With Recurrent Paraganglioma/Pheochromocytoma
NCT00874614	Phase 2	UNKNOWN	A Study Evaluating Ultratrace Iobenguane I131 in Patients With Malignant Relapsed/Refractory Pheochromocytoma/Paraganglioma
NCT00923481	Phase 2	COMPLETED	A Broad Multi-histology Phase II Study of the Multi-Kinase Inhibitor R935788 (Fostamatinib Disodium) in Advanced Colorectal, Non-small Cell Lung, Head and Neck Hepatocellular and Renal Cell Carcinomas, and Pheochromocytoma and Thyroid Tumors (Multi-H…
NCT01152827	Phase 2	COMPLETED	RAD001 in Pheochromocytoma or Nonfunctioning Carcinoid
NCT01413503	Phase 2	COMPLETED	A Phase II Study of 131I- Metaiodobenzylguanidine (MIBG) for Treatment of Metastatic or Unresectable Pheochromocytoma and Related Tumors
NCT01635907	Phase 2	COMPLETED	Dovitinib in Neuroendocrine Tumors
NCT01967576	Phase 2	COMPLETED	Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma
NCT03165721	Phase 2	TERMINATED	A Phase II Trial of the DNA Methyl Transferase Inhibitor, Guadecitabine (SGI-110), in Children and Adults With Wild Type GIST,Pheochromocytoma and Paraganglioma Associated With Succinate Dehydrogenase Deficiency and HLRCC-associated Kidney Cancer
NCT03206060	Phase 2	RECRUITING	Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma
NCT03839498	Phase 2	ACTIVE_NOT_RECRUITING	Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Pheochromocytoma/Paraganglioma
NCT03946527	Phase 2	ACTIVE_NOT_RECRUITING	LAnreotide in Metastatic Pheochromocytoma / PARAganglioma (LAMPARA)
NCT04276597	Phase 2	WITHDRAWN	Phase-II Study of Lu177DOTATOC in Adults With STTR(+)Pulmonary, Pheochromocytoma, Paraganglioma, Unknown Primary, Thymus NETs (PUTNET), or Any Other Non-.GEP-NET.
NCT04320589	Phase 2	COMPLETED	the Effect of Dexmedetomidine and Magnesium Sulfate in Open Resection of Pheochromocytoma
NCT04400474	Phase 2	COMPLETED	Trial of Cabozantinib Plus Atezolizumab in Advanced and Progressive Neoplasms of the Endocrine System. The CABATEN Study
NCT04711135	Phase 2	ACTIVE_NOT_RECRUITING	Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients With GEP-NETs and PPGLs
NCT04924075	Phase 2	RECRUITING	Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Solid Tumors With HIF-2α Related Genetic Alterations (MK-6482-015)
NCT05133349	Phase 2	UNKNOWN	A Prospective Phase II Efficacy and Safety Study of Anlotinib in Metastatic or Locally Advanced Pheochromocytoma/ Paraganglioma : Open-label Single-arm, Exploratory Trial
NCT05883085	Phase 2	UNKNOWN	A Study on the Safety and Effectiveness of Anlotinib for Neoadjuvant Treatment of PPGL
NCT05885386	Phase 2	UNKNOWN	A Study on the Safety and Effectiveness of Temozolomide for Neoadjuvant Treatment of PPGL
NCT06045260	Phase 2	RECRUITING	Receptor Radionuclide Therapy With 177Lu-DOTATOC
NCT06233903	Phase 2	WITHDRAWN	18F-mFBG Expression in Neural Crest Tumors and Organs Innervated by the Sympathetic Nervous System
NCT06429397	Phase 2	NOT_YET_RECRUITING	Anlotinib Combined With Benmelstobart for Advanced Pheochromocytoma
NCT06503146	Phase 2	RECRUITING	18F-Fibroblast Activation Protein Inhibitor ([18F]FAPI-74) PET Imaging for Cancer Detection
NCT06683846	Phase 2	RECRUITING	Ivonescimab in the Treatment of Multiple Advanced Tumors
NCT07167329	Phase 2	RECRUITING	Real-World Effectiveness and Pharmacogenetics of Belzutifan in VHL Syndrome: The BELIEVE-VHL Trial
NCT07680205	Phase 2	RECRUITING	An Experimental Study of Belzutifan Impact on Catecholamine Metabolism
NCT07714551	Phase 2	NOT_YET_RECRUITING	Zanzalintinib in Unresectable and Progressive MPGGs
NCT07743138	Phase 2	NOT_YET_RECRUITING	STOMP OUT: A Phase 2 Study To Evaluate The Effects Of Ivonescimab In Patients With Unresectable/Metastatic Adrenocortical Carcinoma (ACC) Or Unresectable Pheochromocytoma/Paraganglioma (PPGL)
NCT02831179	Phase 1	WITHDRAWN	Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor
NCT03246659	Phase 1	COMPLETED	Radiolabelled CCK-2/Gastrin Receptor Analogue for Personalized Theranostic Strategy in Advanced MTC
NCT06520319	Phase 1	UNKNOWN	Head-to-head Study of 68Ga-MGS5 Versus 68Ga-DOTATATE PET/CT in Patients With Medullary Thyroid Carcinoma
NCT07006727	Phase 1	RECRUITING	Phase I Study of [225Ac]Ac-ETN029 in Patients With Advanced DLL3-expressing Solid Tumors
NCT00002947	Phase 1	TERMINATED	Indium In 111 Pentetreotide in Treating Patients With Refractory Cancer
NCT00004847	Phase 1	RECRUITING	Diagnosis of Pheochromocytoma
NCT00049023	Phase 1	COMPLETED	Radiolabeled Octreotide in Treating Children With Advanced or Refractory Solid Tumors
NCT00339131	Phase 1	COMPLETED	ULTRATRACE Iobenguane I 131 in Patients With Malignant Pheochromocytoma, Paraganglioma, or Metastatic Carcinoid
NCT00655655	Phase 1	COMPLETED	Everolimus and Vatalanib in Treating Patients With Advanced Solid Tumors
NCT01155258	Phase 1	COMPLETED	Temsirolimus and Vinorelbine Ditartrate in Treating Patients With Unresectable or Metastatic Solid Tumors

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for RET across ~30M SureChEMBL compounds — explore on Sugi Predict.