GFRA2

Summary

GFRA2 (GDNF family receptor alpha 2, HGNC:4244) is a protein-coding gene on chromosome 8p21.3, encoding GDNF family receptor alpha-2 (O00451). Receptor for neurturin (NRTN), a growth factor that supports the survival of sympathetic neurons.

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent neurotrophic factors that play key roles in the control of neuron survival and differentiation. The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This encoded protein acts preferentially as a receptor for NTN compared to its other family member, GDNF family receptor alpha 1. This gene is a candidate gene for RET-associated diseases. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2675 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 77 total
• Druggable target: yes
• MANE Select transcript: NM_001495

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4244
Approved symbol	GFRA2
Name	GDNF family receptor alpha 2
Location	8p21.3
Locus type	gene with protein product
Status	Approved
Aliases	RETL2, GDNFRB, NTNRA, TRNR2
Ensembl gene	ENSG00000168546
Ensembl biotype	protein_coding
OMIM	601956
Entrez	2675

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000306793, ENST00000517328, ENST00000517892, ENST00000518077, ENST00000519195, ENST00000520676, ENST00000522071, ENST00000524240, ENST00000878618, ENST00000930225, ENST00000970836

RefSeq mRNA: 3 — MANE Select: NM_001495 NM_001165038, NM_001165039, NM_001495

CCDS: CCDS47816, CCDS55207, CCDS55208

Canonical transcript exons

ENST00000524240 — 9 exons

Exon	Start	End
ENSE00002091077	21690398	21693400
ENSE00002113421	21788120	21788875
ENSE00003513858	21782585	21782899
ENSE00003577819	21705932	21706041
ENSE00003589859	21774972	21775055
ENSE00003611523	21704985	21705125
ENSE00003616299	21702805	21702977
ENSE00003650686	21694464	21694517
ENSE00003784351	21750588	21750942

Expression profiles

Bgee: expression breadth ubiquitous, 192 present calls, max score 88.62.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0485 / max 102.9474, expressed in 255 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
92180	0.3022	115
92178	0.3017	133
92181	0.2284	105
92179	0.1628	78
92184	0.0342	8
92182	0.0193	7

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	88.62	gold quality
Brodmann (1909) area 10	UBERON:0013541	87.96	silver quality
prefrontal cortex	UBERON:0000451	86.02	gold quality
left lobe of thyroid gland	UBERON:0001120	85.20	gold quality
right lobe of thyroid gland	UBERON:0001119	84.33	gold quality
thyroid gland	UBERON:0002046	83.80	gold quality
frontal cortex	UBERON:0001870	83.78	gold quality
oocyte	CL:0000023	83.51	gold quality
right frontal lobe	UBERON:0002810	83.17	gold quality
neocortex	UBERON:0001950	82.95	gold quality
Brodmann (1909) area 9	UBERON:0013540	82.86	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	82.76	gold quality
primary visual cortex	UBERON:0002436	82.57	gold quality
cingulate cortex	UBERON:0003027	82.26	gold quality
anterior cingulate cortex	UBERON:0009835	82.24	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.93	gold quality
Brodmann (1909) area 46	UBERON:0006483	81.33	gold quality
superior frontal gyrus	UBERON:0002661	80.64	gold quality
cerebral cortex	UBERON:0000956	80.35	gold quality
orbitofrontal cortex	UBERON:0004167	80.04	silver quality
spleen	UBERON:0002106	79.12	gold quality
frontal pole	UBERON:0002795	78.67	silver quality
postcentral gyrus	UBERON:0002581	78.52	gold quality
middle temporal gyrus	UBERON:0002771	78.13	gold quality
Brodmann (1909) area 23	UBERON:0013554	77.72	gold quality
cortical plate	UBERON:0005343	77.68	gold quality
occipital lobe	UBERON:0002021	77.19	gold quality
parietal lobe	UBERON:0001872	76.44	gold quality
left testis	UBERON:0004533	75.34	gold quality
right testis	UBERON:0004534	74.67	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RUNX1

miRNA regulators (miRDB)

61 targeting GFRA2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-520A-5P	99.35	66.72	1632

Literature-anchored findings (GeneRIF, showing 16)

• Both GFR alpha2a and GFR alpha2c, but not GFR alpha2b, promote neurite outgrowth in transfected Neuro2A cells. (PMID:17522305)
• GFRalpha-2 were observed within sensory and motor nuclei of cranial nerves, dorsal column nuclei, olivary nuclear complex, reticular formation, pontine nuclei, locus caeruleus, raphe nuclei, substantia nigra, and quadrigeminal plate. (PMID:17825269)
• This study found nominally-significant evidence for interactions between GFRA1, 2 and 3 associated with schizophrenia and clozapine response, consistent with the locations of these three genes within linkage regions for schizophrenia. (PMID:20116071)
• GFRA2 genetic variants, and age, may play a role in susceptibility to tardive dyskinesia. (PMID:20369355)
• Cyclic AMP signalling through PKA but not Epac is essential for neurturin-induced biphasic ERK1/2 activation and neurite outgrowths through GFRalpha2 isoforms. (PMID:21723942)
• The study shows co-localization of RET with GFRA1 and GFRA2 in myenteric ganglia of the adult human colon. (PMID:23881409)
• GFRalpha-2 is associated with severe abdominal pain sensation in pancreatic cancer patients. (PMID:24067900)
• In the cochlea, immunolabeling for GFRalpha-2 receptors was identified mainly in the cell bodies of the spiral neurons than in the nerve fibers. No structures in the organ of Corti were labeled with GFRalpha-2 receptor antibody (PMID:24139947)
• GFRalpha2 is under-expressed in functioning adenomas and over-expressed in non-functioning adenomas, specifically gonadotropinomas (PMID:24402129)
• GFRA2 variants associated with diabetic neuropathic pain. (PMID:24974787)
• The cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase. (PMID:27396331)
• High GFRalpha2 expression level leads to PTEN inactivation via Mir-17-5p up-regulation, promoting pancreatic tumor cell growth and chemoresistance. (PMID:27400681)
• biophysical results show that the relative concentration of GFRa2 on cell surfaces can affect the functional affinity of NRTN through avidity effects. (PMID:29414779)
• A novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 was identified to be associated with disease risk, and expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in GFRA2 tissue. (PMID:29724592)
• GFRA2 was upregulated in human neuroblastoma cells and tissues, and promoted neuroblastoma cell proliferation through interacting with the tumor suppressor PTEN. (PMID:30722993)
• We have reconstituted the complete extracellular region of the RET signaling complex together with Neurturin (NRTN) and GFRalpha2 and determined its structure at 5.7-A resolution by cryo-EM. The proteins form an assembly through RET-GFRalpha2 and RET-NRTN interfaces. (PMID:31392261)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	gfra2a	ENSDARG00000042723
danio_rerio	gfra2b	ENSDARG00000044015
mus_musculus	Gfra2	ENSMUSG00000022103
rattus_norvegicus	Gfra2	ENSRNOG00000014010
drosophila_melanogaster	Gfrl	FBGN0262869
caenorhabditis_elegans		WBGENE00022100

Paralogs (4): GFRA4 (ENSG00000125861), GFRA3 (ENSG00000146013), GFRA1 (ENSG00000151892), GFRAL (ENSG00000187871)

Protein

Protein identifiers

GDNF family receptor alpha-2 — O00451 (reviewed: O00451)

Alternative names: GDNF receptor beta, Neurturin receptor alpha, RET ligand 2, TGF-beta-related neurotrophic factor receptor 2

All UniProt accessions (4): O00451, E5RGR6, E5RJ44, J3KNF0

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for neurturin (NRTN), a growth factor that supports the survival of sympathetic neurons. NRTN-binding leads to autophosphorylation and activation of the RET receptor. Also able to mediate GDNF signaling through the RET tyrosine kinase receptor. Participates in NRTN-induced ‘Ser-727’ phosphorylation of STAT3.

Subunit / interactions. Interacts with NRTN ligand and RET: forms a 2:2:2 ternary complex composed of NRTN ligand, GFRA2 and RET receptor. Also forms a 4:4:4 tetrameric complex composed of 4 copies of NRTN ligand, GFRA2 and RET receptor, which prevents endocytosis of RET. Interacts with SORL1.

Subcellular location. Cell membrane.

Tissue specificity. found in both brain and placenta.

Similarity. Belongs to the GDNFR family.

Isoforms (3)

UniProt ID	Names	Canonical?
O00451-1	1, Long	yes
O00451-2	2, Short
O00451-3	3

RefSeq proteins (3): NP_001158510, NP_001158511, NP_001486* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003438	GDNF_rcpt	Family
IPR003504	GDNF_rcpt_a2	Family
IPR016017	GDNF/GAS1	Domain
IPR017372	Glial_neurotroph_fac_rcpt_a1/2	Family
IPR037193	GDNF_alpha	Homologous_superfamily

Pfam: PF02351

UniProt features (48 total): helix 17, disulfide bond 11, strand 5, glycosylation site 3, splice variant 2, turn 2, signal peptide 1, chain 1, propeptide 1, sequence variant 1, sequence conflict 1, region of interest 1, compositionally biased region 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5MR5	X-RAY DIFFRACTION	2
5MR4	X-RAY DIFFRACTION	2.4
6Q2O	ELECTRON MICROSCOPY	3.65
6Q2R	ELECTRON MICROSCOPY	4.3
6GL7	ELECTRON MICROSCOPY	6.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00451-F1	75.99	0.55

Functional residue map

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

Post-translational modifications (1): 444

Disulfide bonds (11): 95–105, 161–222, 168–174, 185–200, 195–241, 224–229, 251–323, 258–264, 275–293, 285–347, 40–93

Glycosylation sites (3): 52, 357, 413

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-419037	NCAM1 interactions
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-8853659	RET signaling

MSigDB gene sets: 114 (showing top): AGGAAGC_MIR5163P, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOCC_CELL_SURFACE, REACTOME_NCAM_SIGNALING_FOR_NEURITE_OUT_GROWTH, CTAGGAA_MIR384, chr8p21, DELYS_THYROID_CANCER_DN, GOMF_GLYCOSAMINOGLYCAN_BINDING, RIGGI_EWING_SARCOMA_PROGENITOR_UP, HILLION_HMGA1B_TARGETS, GOCC_SIDE_OF_MEMBRANE, GOCC_RECEPTOR_COMPLEX, GOBP_CELL_SURFACE_RECEPTOR_PROTEIN_TYROSINE_KINASE_SIGNALING_PATHWAY, GOCC_EXTRINSIC_COMPONENT_OF_MEMBRANE, GOMF_SULFUR_COMPOUND_BINDING

GO Biological Process (3): cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), nervous system development (GO:0007399), glial cell-derived neurotrophic factor receptor signaling pathway (GO:0035860)

GO Molecular Function (3): glial cell-derived neurotrophic factor receptor activity (GO:0016167), heparan sulfate binding (GO:1904399), signaling receptor activity (GO:0038023)

GO Cellular Component (6): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), extrinsic component of membrane (GO:0019898), signaling receptor complex (GO:0043235), membrane (GO:0016020), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
NCAM signaling for neurite out-growth	1
MAPK1/MAPK3 signaling	1
Axon guidance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
membrane	3
cellular anatomical structure	3
enzyme-linked receptor protein signaling pathway	1
system development	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cytokine receptor activity	1
glial cell-derived neurotrophic factor receptor signaling pathway	1
glycosaminoglycan binding	1
carboxylic acid binding	1
sulfur compound binding	1
molecular transducer activity	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
protein-containing complex	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

1124 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GFRA2	NRTN	Q99748	999
GFRA2	GDNF	P39905	998
GFRA2	ARTN	Q5T4W7	995
GFRA2	PSPN	O60542	994
GFRA2	RET	P07949	994
GFRA2	NTRK1	P04629	841
GFRA2	NTF3	P20783	669
GFRA2	NTF4	P34130	651
GFRA2	NGF	P01138	646
GFRA2	BDNF	P23560	640
GFRA2	TAC1	P20366	634
GFRA2	EDN3	P14138	551
GFRA2	NCAM1	P13591	546
GFRA2	NGFR	P08138	516
GFRA2	GFRA3	O60609	512

IntAct

6 interactions, top by confidence:

A	B	Type	Score
RIMS1	KIF2A	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	POTEF	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	POM121C	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	IGLON5	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): NRTN (Reconstituted Complex), GDNF (Reconstituted Complex), NRTN (Reconstituted Complex), GDNF (Reconstituted Complex), GFRA2 (Affinity Capture-MS), GFRA2 (Affinity Capture-MS)

ESM2 similar proteins: A1XQX1, A2ATD1, B2RZ42, D4A6L0, O00451, O08842, O13097, O13156, O13157, O93512, O95156, O95980, P0DJQ9, P15473, P17936, P20959, P21744, P22692, P24854, P47878, P47879, P52796, P56159, P58659, P97785, Q05716, Q17QD6, Q28145, Q28893, Q58CS8, Q5E9X0, Q5RAD6, Q5T848, Q62997, Q6PCX7, Q6PFE7, Q6S5C2, Q7TQ33, Q80UG6, Q8C419

Diamond homologs: O00451, O08842, O13156, O13157, O35118, O60609, O93512, P56159, P97785, Q5E9X0, Q5RAD6, Q62997, Q9EPI2, Q9GZZ7, Q9JJT2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GDNF	up-regulates	GFRA2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	67
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2039 predictions. Top by Δscore:

Variant	Effect	Δscore
8:21693431:C:CT	acceptor_gain	1.0000
8:21693432:A:T	acceptor_gain	1.0000
8:21693439:A:AC	acceptor_gain	1.0000
8:21702800:CTCAC:C	donor_loss	1.0000
8:21702801:TCA:T	donor_loss	1.0000
8:21702974:TTCC:T	acceptor_gain	1.0000
8:21702975:TCC:T	acceptor_gain	1.0000
8:21702976:CC:C	acceptor_gain	1.0000
8:21702976:CCC:C	acceptor_gain	1.0000
8:21702976:CCCT:C	acceptor_loss	1.0000
8:21702977:CC:C	acceptor_gain	1.0000
8:21702977:CCTG:C	acceptor_loss	1.0000
8:21702978:C:CA	acceptor_loss	1.0000
8:21702978:C:CC	acceptor_gain	1.0000
8:21702983:A:C	acceptor_gain	1.0000
8:21702989:G:C	acceptor_gain	1.0000
8:21702989:G:GC	acceptor_gain	1.0000
8:21704979:ACTT:A	donor_loss	1.0000
8:21704981:TTAC:T	donor_loss	1.0000
8:21704982:TAC:T	donor_loss	1.0000
8:21704983:A:AC	donor_gain	1.0000
8:21704983:A:C	donor_loss	1.0000
8:21704984:C:CG	donor_gain	1.0000
8:21704984:CG:C	donor_gain	1.0000
8:21704984:CGG:C	donor_gain	1.0000
8:21704984:CGGA:C	donor_gain	1.0000
8:21704984:CGGAG:C	donor_gain	1.0000
8:21705124:CC:C	acceptor_gain	1.0000
8:21705125:CC:C	acceptor_gain	1.0000
8:21705126:C:T	acceptor_gain	1.0000

AlphaMissense

3048 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:21750685:G:T	R233S	1.000
8:21750860:G:C	C174W	1.000
8:21750861:C:G	C174S	1.000
8:21750861:C:T	C174Y	1.000
8:21750862:A:G	C174R	1.000
8:21750862:A:T	C174S	1.000
8:21750878:G:C	C168W	1.000
8:21750879:C:G	C168S	1.000
8:21750879:C:T	C168Y	1.000
8:21750880:A:G	C168R	1.000
8:21750880:A:T	C168S	1.000
8:21782610:C:A	W110C	1.000
8:21782610:C:G	W110C	1.000
8:21782625:A:C	C105W	1.000
8:21782626:C:G	C105S	1.000
8:21782627:A:G	C105R	1.000
8:21782627:A:T	C105S	1.000
8:21782655:G:C	C95W	1.000
8:21782656:C:G	C95S	1.000
8:21782657:A:G	C95R	1.000
8:21782657:A:T	C95S	1.000
8:21782661:G:C	C93W	1.000
8:21782663:A:G	C93R	1.000
8:21782707:C:G	C78S	1.000
8:21782708:A:G	C78R	1.000
8:21782708:A:T	C78S	1.000
8:21782751:G:C	C63W	1.000
8:21782752:C:G	C63S	1.000
8:21782753:A:G	C63R	1.000
8:21782753:A:T	C63S	1.000

dbSNP variants (sampled 300 via entrez): RS1000019854 (8:21736065 C>T), RS1000023979 (8:21704676 A>C), RS1000040096 (8:21746950 C>A,T), RS1000055888 (8:21774581 T>G), RS1000063728 (8:21727560 G>A,C), RS1000078046 (8:21741518 T>A), RS1000085995 (8:21693753 GAGA>G), RS1000090674 (8:21746723 C>T), RS1000118511 (8:21704523 T>C), RS1000174320 (8:21760459 G>C), RS1000176037 (8:21814224 G>T), RS1000184137 (8:21709175 T>C), RS1000207910 (8:21779357 T>C), RS1000219695 (8:21808965 A>G), RS1000221963 (8:21712857 A>C)

Disease associations

OMIM: gene MIM:601956 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002080_19	Migraine with aura	8.000000e-08
GCST002507_1	Neuropathic pain in type 2 diabetes	2.000000e-07
GCST002701_26	Verbal declarative memory	2.000000e-06
GCST002875_22	Diisocyanate-induced asthma	1.000000e-06
GCST002875_81	Diisocyanate-induced asthma	2.000000e-06
GCST003225_30	Pelvic organ prolapse (moderate/severe)	7.000000e-07
GCST006148_6	Frontotemporal dementia with GRN mutation	1.000000e-07
GCST006154_4	Frontotemporal dementia	2.000000e-08
GCST006585_2064	Blood protein levels	5.000000e-39
GCST008154_64	Trunk fat mass	5.000000e-06
GCST010105_14	Nicotine dependence symptom count	7.000000e-07
GCST010105_86	Nicotine dependence symptom count	7.000000e-07
GCST011750_2	Response to lithium treatment in bipolar disorder (continuous phenotype)	2.000000e-07

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005762	neuropathic pain
EFO:0004874	memory performance
EFO:0006805	word list delayed recall measurement
EFO:0006995	response to diisocyanate
EFO:0009262	nicotine dependence symptom count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066244 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1128397	GFRA2		0.00	0
rs4567028	GFRA2		0.00	0
rs13250096	GFRA2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — GDNF Family Receptor (GFR)

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.00	IC50	100	nM	CHEMBL5596770
6.00	IC50	1000	nM	CHEMBL5591042
5.60	IC50	2500	nM	CHEMBL5597875
5.43	IC50	3700	nM	CHEMBL5597536
5.00	IC50	9900	nM	CHEMBL5598111

PubChem BioAssay actives

5 with measured affinity, of 32 total; 5 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
(2R)-2-[[2-[3-[[(2R)-5-(2-anilinopyrimidin-5-yl)-2,3-dihydro-1H-inden-2-yl]oxy]phenyl]acetyl]amino]-2-cyclohexyl-N-methylacetamide	2120387: Inhibition of GFRalpha2 (unknown origin)	ic50	0.1000	uM
(2R)-2-[[2-[3-[[(1S)-5-(2-anilinopyrimidin-5-yl)-2,3-dihydro-1H-inden-1-yl]oxy]phenyl]acetyl]amino]-2-cyclohexyl-N-methylacetamide	2120387: Inhibition of GFRalpha2 (unknown origin)	ic50	1.0000	uM
(2R)-2-[[2-[3-[[(1S)-5-(5-anilinopyrimidin-2-yl)-2,3-dihydro-1H-inden-1-yl]oxy]phenyl]acetyl]amino]-2-cyclohexylacetamide	2120387: Inhibition of GFRalpha2 (unknown origin)	ic50	2.5000	uM
(2S)-2-[[2-[3-[[(1S)-5-(2-anilinopyrimidin-5-yl)-2,3-dihydro-1H-inden-1-yl]oxy]phenyl]acetyl]amino]-3-(1H-imidazol-5-yl)-N-methylpropanamide	2120387: Inhibition of GFRalpha2 (unknown origin)	ic50	3.7000	uM
(2R)-2-cyclohexyl-2-[[2-[3-[[(1S)-2,3-dihydro-1H-inden-1-yl]oxy]phenyl]acetyl]amino]-N-methylacetamide	2120387: Inhibition of GFRalpha2 (unknown origin)	ic50	9.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	7
Benzo(a)pyrene	increases methylation, affects methylation, decreases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
bisphenol A	affects cotreatment, increases methylation	1
ethyl-p-hydroxybenzoate	decreases expression	1
cobaltous chloride	decreases expression	1
pyrrolidine dithiocarbamic acid	affects cotreatment, decreases expression, decreases reaction	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	increases methylation	1
bathocuproine sulfonate	affects cotreatment, decreases expression, decreases reaction	1
ferrous chloride	decreases expression	1
aflatoxin B2	increases methylation	1
nickel sulfate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
Resveratrol	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Allergens	increases expression	1
Atrazine	decreases expression	1
Carbamazepine	affects expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression, increases reaction, affects cotreatment, decreases reaction	1
Hydralazine	affects cotreatment, increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Methapyrilene	increases methylation	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5585986	Binding	Inhibition of GFRalpha2 (unknown origin)	Discovery of the first selective, small-molecule GFRα2/3 inhibitors through DNA-encoded library technology. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.