multiple endocrine neoplasia type 2B

Summary

multiple endocrine neoplasia type 2B (MONDO:0008082) is a disease caused by RET (GenCC Definitive), with 1 cohort gene and 5 clinical trials. Top therapeutic interventions include sorafenib, vandetanib, and veliparib.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: RET (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 418
• Clinical trials: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple endocrine neoplasia type 2B
Mondo ID	MONDO:0008082
MeSH	D018814
OMIM	162300
Orphanet	247709
DOID	DOID:10016
ICD-11	1754393919
NCIT	C3227
SNOMED CT	61530001
UMLS	C0025269
MedGen	9959
GARD	0010225
MedDRA	10056420
Is cancer (heuristic)	no

Also known as: men 2B · men IIB · men type 2B · men type IIB · MEN2B · multiple endocrine adenomatosis type IIB · multiple endocrine neoplasia IIB · multiple endocrine neoplasia type 2B · multiple endocrine neoplasia type 3 · multiple endocrine neoplasia type IIB · multiple endocrine neoplasia type III · multiple endocrine neoplasia, type 3 (formerly) · multiple endocrine neoplasia, type IIB · multiple endocrine neoplasia, type III · Neuromata, mucosal, with endocrine tumours · RET-related multiple endocrine neoplasia type 2B · Wagenmann-Froboese syndrome

Data availability: 418 ClinVar variants · 4 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › multiple endocrine neoplasia type 2B

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

418 retrieved; paginated sample, class counts are floors:

153 conflicting classifications of pathogenicity, 145 uncertain significance, 52 benign/likely benign, 36 likely benign, 12 pathogenic, 9 benign, 8 pathogenic/likely pathogenic, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13945	NM_020975.4(RET):c.[2410G>A;2711C>G]		Pathogenic	no assertion criteria provided
13905	NM_020975.6(RET):c.1852T>G (p.Cys618Gly)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13909	NM_020975.6(RET):c.1901G>A (p.Cys634Tyr)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13910	NM_020975.6(RET):c.1901G>C (p.Cys634Ser)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13916	NM_020975.6(RET):c.1859G>A (p.Cys620Tyr)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13917	NM_020975.6(RET):c.1900T>C (p.Cys634Arg)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13919	NM_020975.6(RET):c.2753T>C (p.Met918Thr)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13928	NM_020975.6(RET):c.1859G>T (p.Cys620Phe)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13929	NM_020975.6(RET):c.1852T>C (p.Cys618Arg)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13946	NM_020975.6(RET):c.2410G>T (p.Val804Leu)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13951	NM_020975.6(RET):c.2671T>G (p.Ser891Ala)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
230926	NM_020975.6(RET):c.1998G>C (p.Lys666Asn)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
24929	NM_020975.6(RET):c.1947G>A (p.Ser649=)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
24931	NM_020975.6(RET):c.1996A>G (p.Lys666Glu)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
24932	NM_020975.6(RET):c.1998G>T (p.Lys666Asn)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
37102	NM_020975.6(RET):c.2410G>A (p.Val804Met)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38611	NM_020975.6(RET):c.2304G>T (p.Glu768Asp)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
38612	NM_020975.6(RET):c.2370G>T (p.Leu790Phe)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
38629	NM_020975.6(RET):c.2647_2648delinsTT (p.Ala883Phe)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
932072	NM_020975.6(RET):c.2631del (p.Arg878fs)	RET	Pathogenic	criteria provided, single submitter
13922	NM_020975.6(RET):c.2914A>G (p.Arg972Gly)	RET	Likely pathogenic	criteria provided, single submitter
3595005	NM_020975.6(RET):c.2672C>T (p.Ser891Leu)	RET	Likely pathogenic	criteria provided, single submitter
986727	NM_020975.6(RET):c.1893_1898del (p.Asp631_Leu633delinsGlu)	RET	Likely pathogenic	criteria provided, single submitter
229201	NM_020975.6(RET):c.-2C>A	LOC106736614	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
477374	NM_020975.6(RET):c.-37G>C	LOC106736614	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
486313	NM_020975.6(RET):c.20G>A (p.Gly7Asp)	LOC106736614	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1008125	NM_020975.6(RET):c.1828A>C (p.Asn610His)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1149781	NM_020975.6(RET):c.96G>T (p.Ser32=)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1201517	NM_020975.6(RET):c.1264-5C>A	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
132727	NM_020975.6(RET):c.3057G>A (p.Ala1019=)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RET	Definitive	Autosomal dominant	multiple endocrine neoplasia type 2B	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RET	Orphanet:146	Differentiated thyroid carcinoma
RET	Orphanet:1848	Renal agenesis, bilateral
RET	Orphanet:247698	Multiple endocrine neoplasia type 2A
RET	Orphanet:247709	Multiple endocrine neoplasia type 2B
RET	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
RET	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
RET	Orphanet:388	Hirschsprung disease
RET	Orphanet:93100	Renal agenesis, unilateral
RET	Orphanet:99361	Isolated familial medullary thyroid carcinoma
RET	Orphanet:99803	Haddad syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RET	HGNC:9967	ENSG00000165731	P07949	Proto-oncogene tyrosine-protein kinase receptor Ret	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RET	Proto-oncogene tyrosine-protein kinase receptor Ret	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,…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal root ganglion	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RET	193	broad	marker	substantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RET	4,203

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RET	P07949	34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the nephric duct	1	634.4×	0.003	RET
NPAS4 regulates expression of target genes	1	496.5×	0.003	RET
Formation of the ureteric bud	1	496.5×	0.003	RET
RET signaling	1	259.6×	0.005	RET
RAF/MAP kinase cascade	1	61.1×	0.016	RET

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic epithelial tube formation	1	8426.0×	0.001	RET
posterior midgut development	1	8426.0×	0.001	RET
positive regulation of metanephric glomerulus development	1	5617.3×	0.001	RET
ureter maturation	1	4213.0×	0.001	RET
Peyer’s patch morphogenesis	1	4213.0×	0.001	RET
GDF15-GFRAL signaling pathway	1	4213.0×	0.001	RET
lymphocyte migration into lymphoid organs	1	1872.4×	0.002	RET
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	1532.0×	0.002	RET
positive regulation of cell size	1	1296.3×	0.002	RET
glial cell-derived neurotrophic factor receptor signaling pathway	1	1203.7×	0.002	RET
membrane protein proteolysis	1	1053.2×	0.002	RET
positive regulation of cell adhesion mediated by integrin	1	1053.2×	0.002	RET
neuron cell-cell adhesion	1	991.3×	0.002	RET
enteric nervous system development	1	991.3×	0.002	RET
response to pain	1	887.0×	0.002	RET
regulation of axonogenesis	1	887.0×	0.002	RET
neuron maturation	1	802.5×	0.002	RET
ureteric bud development	1	455.5×	0.004	RET
neural crest cell migration	1	337.0×	0.005	RET
regulation of cell adhesion	1	306.4×	0.005	RET
cellular response to retinoic acid	1	234.1×	0.007	RET
cell surface receptor protein tyrosine kinase signaling pathway	1	173.7×	0.008	RET
MAPK cascade	1	153.2×	0.009	RET
homophilic cell-cell adhesion	1	140.4×	0.009	RET
positive regulation of neuron projection development	1	137.0×	0.009	RET
axon guidance	1	90.6×	0.014	RET
positive regulation of MAPK cascade	1	80.6×	0.015	RET
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	78.4×	0.015	RET
positive regulation of cell migration	1	61.7×	0.018	RET
positive regulation of gene expression	1	38.7×	0.028	RET

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RET	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RET	135	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
VANDETANIB	4	RET
NILOTINIB	4	RET
BOSUTINIB	4	RET
GILTERITINIB	4	RET
BRIGATINIB	4	RET
UPADACITINIB	4	RET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RET	1,586	Binding:1573, Functional:10, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RET	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
RET	1,586

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

28 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
NILOTINIB	4	RET
BOSUTINIB	4	RET
GILTERITINIB	4	RET
BRIGATINIB	4	RET
UPADACITINIB	4	RET

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RET
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE2	1
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00390325	PHASE2	COMPLETED	Sorafenib Tosylate in Treating Patients With Metastatic, Locally Advanced, or Recurrent Medullary Thyroid Cancer
NCT00514046	PHASE1/PHASE2	COMPLETED	Vandetanib to Treat Children and Adolescents With Medullary Thyroid Cancer
NCT02831179	PHASE1	WITHDRAWN	Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SORAFENIB	4	1
VANDETANIB	4	1
VELIPARIB	3	2