multiple endocrine neoplasia type 2A

Summary

multiple endocrine neoplasia type 2A (MONDO:0008234) is a disease caused by RET (GenCC Definitive), with 4 cohort genes and 4 clinical trials. Top therapeutic interventions include sorafenib, vandetanib, and veliparib.

At a glance

• Causal gene: RET (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 781
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple endocrine neoplasia type 2A
Mondo ID	MONDO:0008234
MeSH	D018813
OMIM	171400
Orphanet	247698
DOID	DOID:0050430
ICD-11	1689268035
NCIT	C3226
SNOMED CT	721188000
UMLS	C0025268
MedGen	9958
GARD	0004881
Is cancer (heuristic)	no

Also known as: MEA type 2a · MEA type II · men 2A · men type 2a · men type II · men-2A syndrome · MEN2A · multiple endocrine adenomatosis type 2A · multiple endocrine adenomatosis type 2a · multiple endocrine adenomatosis type II · multiple endocrine adenomatosis, type II · multiple endocrine neoplasia IIA · multiple endocrine neoplasia type 2A · multiple endocrine neoplasia type II · multiple endocrine neoplasia, type II · multiple endocrine neoplasia, type IIA · pheochromocytoma and amyloid producing medullary thyroid carcinoma · ptc syndrome · RET-related multiple endocrine neoplasia type 2A · Sipple syndrome

Data availability: 781 ClinVar variants · 3 GenCC gene-disease records · 5 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 2A

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, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, 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

600 retrieved; paginated sample, class counts are floors:

167 conflicting classifications of pathogenicity, 155 benign/likely benign, 107 uncertain significance, 85 likely benign, 38 benign, 30 pathogenic, 12 pathogenic/likely pathogenic, 6 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13906	NM_020975.4(RET):c.[1896G>C;1897C>G;1900T>C]		Pathogenic	no assertion criteria provided
1372611	NM_020975.6(RET):c.1826G>C (p.Cys609Ser)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13905	NM_020975.6(RET):c.1852T>G (p.Cys618Gly)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13908	NM_020975.6(RET):c.1900T>G (p.Cys634Gly)	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
13911	NM_020975.6(RET):c.1901G>T (p.Cys634Phe)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13913	NM_020975.6(RET):c.1833C>G (p.Cys611Trp)	RET	Pathogenic	criteria provided, single submitter
13914	NM_020975.6(RET):c.1853G>C (p.Cys618Ser)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13915	NM_020975.6(RET):c.1858T>C (p.Cys620Arg)	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
13918	NM_020975.6(RET):c.1902C>G (p.Cys634Trp)	RET	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
13933	NM_020975.6(RET):c.1826G>A (p.Cys609Tyr)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13935	NM_020975.6(RET):c.2370G>C (p.Leu790Phe)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13942	NM_020975.6(RET):c.1919C>G (p.Ala640Gly)	RET	Pathogenic	no assertion criteria provided
13943	NM_020975.6(RET):c.1859G>C (p.Cys620Ser)	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
13950	NM_020975.6(RET):c.1597G>T (p.Gly533Cys)	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
24896	NM_020975.6(RET):c.1831T>C (p.Cys611Arg)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
24899	NM_020975.6(RET):c.1832G>T (p.Cys611Phe)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
24901	NM_020975.6(RET):c.1853G>A (p.Cys618Tyr)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
24902	NM_020975.6(RET):c.1853G>T (p.Cys618Phe)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
24905	NM_020975.6(RET):c.1858T>G (p.Cys620Gly)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
24909	NM_020975.6(RET):c.1889G>A (p.Cys630Tyr)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 26 · 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
SDHA	Orphanet:139411	Carney triad
SDHA	Orphanet:154	Familial isolated dilated cardiomyopathy
SDHA	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHA	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHA	Orphanet:44890	Gastrointestinal stromal tumor
SDHA	Orphanet:97286	Carney-Stratakis syndrome
KIF1B	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
KIF1B	Orphanet:99946	Autosomal dominant Charcot-Marie-Tooth disease type 2A1
ALK	Orphanet:146	Differentiated thyroid carcinoma
ALK	Orphanet:178342	Inflammatory myofibroblastic tumor
ALK	Orphanet:251877	Ganglioneuroblastoma
ALK	Orphanet:251992	Ganglioneuroma
ALK	Orphanet:300895	ALK-positive anaplastic large cell lymphoma
ALK	Orphanet:364043	ALK-positive large B-cell lymphoma
ALK	Orphanet:626	Large/giant congenital melanocytic nevus
ALK	Orphanet:635	Neuroblastoma

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RET	HGNC:9967	ENSG00000165731	P07949	Proto-oncogene tyrosine-protein kinase receptor Ret	gencc,clinvar
SDHA	HGNC:10680	ENSG00000073578	P31040	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	clinvar
KIF1B	HGNC:16636	ENSG00000054523	O60333	Kinesin-like protein KIF1B	clinvar
ALK	HGNC:427	ENSG00000171094	Q9UM73	ALK tyrosine kinase receptor	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,…
SDHA	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
KIF1B	Kinesin-like protein KIF1B	Has a plus-end-directed microtubule motor activity and functions as a motor for transport of vesicles and organelles along microtubules.
ALK	ALK tyrosine kinase receptor	Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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	2	13.9×	0.022
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	1	0.5×	0.962

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
SDHA	Other/Unknown	no		FRD_SDH_FAD_BS, FAD-dep_OxRdtase_2_FAD-bd, Succ_DH_flav_su_fwd
KIF1B	Scaffold/PPI	no		FHA_dom, Kinesin_motor_dom, PH_domain
ALK	Kinase	yes	2.7.10.1	Prot_kinase_dom, MAM_dom, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal root ganglion	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1
apex of heart	1
heart left ventricle	1
mucosa of transverse colon	1
biceps brachii	1
medial globus pallidus	1
skeletal muscle tissue of rectus abdominis	1
male germ cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
sperm	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
SDHA	143	ubiquitous	marker	apex of heart, heart left ventricle, mucosa of transverse colon
KIF1B	287	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, medial globus pallidus
ALK	181	broad	marker	sperm, male germ cell, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDHA	6,141
ALK	4,792
RET	4,203
KIF1B	2,257

Intra-cohort edges

A	B	Sources
ALK	RET	intact
KIF1B	RET	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALK	Q9UM73	79
RET	P07949	34
SDHA	P31040	5
KIF1B	O60333	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Drug resistance of ALK mutants	1	2855.0×	0.002	ALK
ASP-3026-resistant ALK mutants	1	2855.0×	0.002	ALK
NVP-TAE684-resistant ALK mutants	1	2855.0×	0.002	ALK
alectinib-resistant ALK mutants	1	2855.0×	0.002	ALK
brigatinib-resistant ALK mutants	1	2855.0×	0.002	ALK
ceritinib-resistant ALK mutants	1	2855.0×	0.002	ALK
crizotinib-resistant ALK mutants	1	2855.0×	0.002	ALK
lorlatinib-resistant ALK mutants	1	2855.0×	0.002	ALK
MDK and PTN in ALK signaling	1	713.8×	0.005	ALK
ALK mutants bind TKIs	1	237.9×	0.015	ALK
Formation of the nephric duct	1	158.6×	0.019	RET
Signaling by ALK	1	142.8×	0.019	ALK
Maturation of TCA enzymes and regulation of TCA cycle	1	142.8×	0.019	SDHA
NPAS4 regulates expression of target genes	1	124.1×	0.019	RET
Formation of the ureteric bud	1	124.1×	0.019	RET
Citric acid cycle (TCA cycle)	1	105.7×	0.021	SDHA
Signaling by ALK in cancer	1	68.0×	0.030	ALK
RET signaling	1	64.9×	0.030	RET
Kinesins	1	44.6×	0.041	KIF1B
Signaling by ALK fusions and activated point mutants	1	37.6×	0.046	ALK
Golgi-to-ER retrograde transport	1	33.2×	0.050	KIF1B
COPI-dependent Golgi-to-ER retrograde traffic	1	27.7×	0.057	KIF1B
Intra-Golgi and retrograde Golgi-to-ER traffic	1	26.2×	0.057	KIF1B
Respiratory electron transport	1	23.8×	0.060	SDHA
Aerobic respiration and respiratory electron transport	1	22.1×	0.062	SDHA
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.079	KIF1B
RAF/MAP kinase cascade	1	15.3×	0.083	RET
Diseases of signal transduction by growth factor receptors and second messengers	1	14.2×	0.086	ALK
Signaling by Receptor Tyrosine Kinases	1	12.9×	0.091	ALK
Membrane Trafficking	1	9.3×	0.120	KIF1B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 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	2106.5×	0.006	RET
posterior midgut development	1	2106.5×	0.006	RET
response to environmental enrichment	1	2106.5×	0.006	ALK
positive regulation of metanephric glomerulus development	1	1404.3×	0.006	RET
ureter maturation	1	1053.2×	0.006	RET
regulation of dopamine receptor signaling pathway	1	1053.2×	0.006	ALK
Peyer’s patch morphogenesis	1	1053.2×	0.006	RET
GDF15-GFRAL signaling pathway	1	1053.2×	0.006	RET
succinate metabolic process	1	842.6×	0.006	SDHA
mitochondrial electron transport, succinate to ubiquinone	1	842.6×	0.006	SDHA
swimming behavior	1	842.6×	0.006	ALK
retrograde neuronal dense core vesicle transport	1	842.6×	0.006	KIF1B
cell surface receptor protein tyrosine kinase signaling pathway	2	86.9×	0.006	RET, ALK
response to stress	1	601.9×	0.007	ALK
peptidyl-tyrosine autophosphorylation	1	468.1×	0.008	ALK
lymphocyte migration into lymphoid organs	1	468.1×	0.008	RET
neuron-neuron synaptic transmission	1	421.3×	0.008	KIF1B
apoptotic process involved in development	1	421.3×	0.008	KIF1B
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	383.0×	0.009	RET
mitochondrion transport along microtubule	1	351.1×	0.009	KIF1B
phosphorylation	1	324.1×	0.009	ALK
positive regulation of cell size	1	324.1×	0.009	RET
glial cell-derived neurotrophic factor receptor signaling pathway	1	300.9×	0.009	RET
membrane protein proteolysis	1	263.3×	0.009	RET
positive regulation of cell adhesion mediated by integrin	1	263.3×	0.009	RET
neuron cell-cell adhesion	1	247.8×	0.009	RET
enteric nervous system development	1	247.8×	0.009	RET
anterograde synaptic vesicle transport	1	247.8×	0.009	KIF1B
positive regulation of dendrite development	1	247.8×	0.009	ALK
response to pain	1	221.7×	0.009	RET

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 4 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
SDHA	LINEZOLID
ALK	CERITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RET	135	4
ALK	61	4
SDHA	1	4
KIF1B	0	0

Drugs targeting cohort genes (top 30)

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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ALK	1,815	Binding:1801, Functional:13, ADMET:1
RET	1,586	Binding:1573, Functional:10, ADMET:3
SDHA	3	Binding:3
KIF1B	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RET	2.7.10.1	receptor protein-tyrosine kinase
ALK	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
ALK	1,815

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	ALK, RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	ALK, RET
RUXOLITINIB	4	ALK, RET
INFIGRATINIB PHOSPHATE	4	ALK, RET
INFIGRATINIB	4	ALK, RET
IBRUTINIB	4	RET
PALBOCICLIB	4	ALK, RET
REGORAFENIB	4	RET
ENTRECTINIB	4	ALK, RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	ALK, RET
NILOTINIB	4	RET
BOSUTINIB	4	ALK, RET
GILTERITINIB	4	ALK, RET
BRIGATINIB	4	ALK, RET
UPADACITINIB	4	ALK, RET

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	RET, SDHA, ALK
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	1	KIF1B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KIF1B	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

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

Drugs tested across these trials (top 30)

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