Melanoma

Summary

Melanoma (MONDO:0005105) is a cancer (an umbrella term covering 15 Mondo subtypes) with 75 cohort genes (201 GWAS associations across 44 studies; 52 CIViC-evidence somatic drivers; 21 ClinVar predisposition records) and 2,417 clinical trials. The dominant Reactome pathway is RAF/MAP kinase cascade (12 cohort genes). Molecularly, BRAF V600E confers sensitivity to Dabrafenib in Melanoma (CIViC Level A); 201 further subtype–drug associations are mapped below. Top therapeutic interventions include dacarbazine, dabrafenib, and vemurafenib.

At a glance

• Classification: Cancer
• Umbrella term: 15 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 201
• ClinVar variants: 21
• Clinical trials: 2,417
• Precision-medicine evidence (CIViC): 202 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	melanoma
Mondo ID	MONDO:0005105
EFO	EFO:0000756
MeSH	D008545
Orphanet	411533
DOID	DOID:1909
NCIT	C3224
SNOMED CT	372244006
UMLS	C0025202
MedGen	9944
Is cancer (heuristic)	yes

Also known as: malignant melanoma · melanoma · melanoma (disease) · melanoma, malignant

Data availability: 21 ClinVar variants · 201 GWAS associations (44 studies) · 2 GenCC gene-disease records · 1 HPO phenotype · 2,236 cell lines · 83 intOGen driver records.

Disease family

An umbrella term covering 15 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › melanocytic neoplasm › melanoma

Related subtypes (2): central nervous system melanocytic neoplasm, melanocytic skin neoplasm

Subtypes (15): scrotum melanoma, amelanotic melanoma, epithelioid cell melanoma, malignant breast melanoma, melanomatosis, cutaneous melanoma, metastatic melanoma, non-cutaneous melanoma, ocular melanoma, spindle cell melanoma, mixed epithelioid and spindle cell melanoma, malignant melanoma of the mucosa, familial melanoma, CDK4 linked melanoma, childhood malignant melanoma

Genetics & variants

GWAS landscape

201 GWAS associations across 44 studies. Top hits map to 34 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1805007	2e-72	MC1R	T	0.43
rs35026726	4e-61	ZNF276	T	1.55
rs74800773	2e-39	DEF8	?
rs6059655	3e-38	RALY	A	1.41
rs869330	3e-35	MTAP	A	0.2
Affx-35293625	5e-35		?	1.55
rs75570604	7e-34	FANCA	C	0.42
rs56238684	2e-33	PIGU	C	1.39
rs12931267	1e-32	FANCA	?	1.53
rs1126809	6e-31	TYR	A	0.2
rs871024	6e-29	MTAP	C	1.22
rs4408545	1e-28	AFG3L1P, AFG3L1P	C	1.22
rs2425025	4e-28	MMP24OS, MMP24	G	1.38
rs258322	3e-27	CDK10	A	1.67
rs31490	1e-26	CLPTM1L	A	0.17
rs4499232	9e-26	SPG7	T	1.21
rs12203592	3e-25	IRF4	?
rs2280374	2e-24	DPEP1	?	1.46
rs77270200	5e-24	GAS8	?	1.45
rs16891982	1e-23	SLC45A2	?	2.38
rs74836424	1e-22	ANKRD11	?	1.47
rs4785763	6e-22	AFG3L1P, AFG3L1P	A	1.36
rs17401449	3e-20	SNTA1 - CBFA2T2	G	1.31
rs35407	2e-19	SLC45A2	G	2.08
rs1204552	3e-19	NORAD	A	1.34
rs1885120	2e-18	MYH7B	C	1.55
rs201131773	3e-17	MTAP	?	1.19
rs401681	7e-16	CLPTM1L	?	1.23
rs910873	1e-15	PIGU	T	1.75
rs958219	8e-15	RN7SL151P - MTAP	T	0.19

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90558253	Ingold N	2024	10,552	735,194	Exploring the Germline Genetics of In Situ and Invasive Cutaneous Melanoma: A Genome-Wide Association Study Meta-Analysis.
GCST90011809	Rashkin SR	2020	6,777	410,350	Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts.
GCST004142	Ransohoff KJ	2017	4,842	286,565	Two-stage genome-wide association study identifies a novel susceptibility locus associated with melanoma.
GCST90503280	Wilcox N	2025	4,210	415,097	The contribution of coding variants to the heritability of multiple cancer types using UK Biobank whole-exome sequencing data.
GCST90103972	Liyanage U	2021	4,089	11,901	Multi-trait genetic analysis identifies auto-immune loci associated with cutaneous melanoma.
GCST90077638	Backman JD	2021	3,595	36,019	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90081624	Backman JD	2021	3,595	36,019	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90558252	Ingold N	2024	3,564	734,933	Exploring the Germline Genetics of In Situ and Invasive Cutaneous Melanoma: A Genome-Wide Association Study Meta-Analysis.
GCST90041914	Jiang L	2021	3,564	452,712	A generalized linear mixed model association tool for biobank-scale data.
GCST90027057	Brandes N	2021	3,122	271,708	Genetic association studies of alterations in protein function expose recessive effects on cancer predisposition.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	4
Tier 2: splice/UTR	2
Tier 3: regulatory	0
Tier 4: intronic/intergenic	44

MAF distribution

Bucket	Variants
common (>=0.05)	45
low_freq (0.01-0.05)	4
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intron_variant	36
missense_variant	4
intergenic_variant	4
unknown	2
non_coding_transcript_exon_variant	2
splice_region_variant	1
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1805007	16	89919709	C>A,G,T	0.1	missense_variant	MC1R	2e-72	Tier 1: coding
rs35026726	16	89724871	C>T	0.05	intron_variant	ZNF276	4e-61	Tier 4: intronic/intergenic
rs74800773	16	89958562	C>A,G,T	0.05	intron_variant	DEF8	2e-39	Tier 4: intronic/intergenic
rs6059655	20	34077942	A>G	0.05	intron_variant	RALY	3e-38	Tier 4: intronic/intergenic
rs869330	9	21804618	A>C,G	0.48	intron_variant	MTAP	3e-35	Tier 4: intronic/intergenic
Affx-35293625							5e-35	Tier 4: intronic/intergenic
rs75570604	16	89780269	G>C	0.103	intron_variant	FANCA	7e-34	Tier 4: intronic/intergenic
rs56238684	20	34648892	G>C	0.05	intron_variant	PIGU	2e-33	Tier 4: intronic/intergenic
rs12931267	16	89752324	C>G	0.05	intron_variant	FANCA	1e-32	Tier 4: intronic/intergenic
rs1126809	11	89284793	G>A	0.3	missense_variant	TYR	6e-31	Tier 1: coding
rs871024	9	21803881	C>A,G	0.05	intron_variant	MTAP	6e-29	Tier 4: intronic/intergenic
rs4408545	16	89977620	C>G,T	0.05	intron_variant	AFG3L1P, AFG3L1P	1e-28	Tier 4: intronic/intergenic
rs2425025	20	35259351	G>A	0.05	intron_variant	MMP24OS, MMP24	4e-28	Tier 4: intronic/intergenic
rs258322	16	89689495	A>C,G,T	0.09	intron_variant	CDK10	3e-27	Tier 4: intronic/intergenic
rs31490	5	1344343	G>A,T	0.44	splice_region_variant	CLPTM1L	1e-26	Tier 2: splice/UTR
rs4499232	16	89510099	T>A,C,G	0.05	intron_variant	SPG7	9e-26	Tier 4: intronic/intergenic
rs12203592	6	396321	C>G,T	0.05	intron_variant	IRF4	3e-25	Tier 4: intronic/intergenic
rs2280374	16	89620999	C>G,T	0.05	intron_variant	DPEP1	2e-24	Tier 4: intronic/intergenic
rs77270200	16	90026667	G>A,C	0.05	intron_variant	GAS8	5e-24	Tier 4: intronic/intergenic
rs16891982	5	33951588	C>A,G	0.04	missense_variant	SLC45A2	1e-23	Tier 1: coding
rs74836424	16	89440922	C>A,T	0.05	intron_variant	ANKRD11	1e-22	Tier 4: intronic/intergenic
rs4785763	16	90000528	A>C,T	0.32	non_coding_transcript_exon_variant	AFG3L1P, AFG3L1P	6e-22	Tier 4: intronic/intergenic
rs17401449	20	33480139	A>G	0.05	intergenic_variant	SNTA1 - CBFA2T2	3e-20	Tier 4: intronic/intergenic
rs35407	5	33946466	A>C,G	0.05	3_prime_UTR_variant	SLC45A2	2e-19	Tier 2: splice/UTR
rs1204552	20	36050981	T>A,C,G	0.05	intron_variant	NORAD	3e-19	Tier 4: intronic/intergenic
rs1885120	20	34989186	C>G,T	0.07	intron_variant	MYH7B	2e-18	Tier 4: intronic/intergenic
rs201131773	9	21805208	A>AAC	0.48	intron_variant	MTAP	3e-17	Tier 4: intronic/intergenic
rs401681	5	1321972	C>T	0.05	intron_variant	CLPTM1L	7e-16	Tier 4: intronic/intergenic
rs910873	20	34583968	G>A,C	0.09	intron_variant	PIGU	1e-15	Tier 4: intronic/intergenic
rs958219	9	21784226	T>C	0.49	intron_variant	RN7SL151P - MTAP	8e-15	Tier 4: intronic/intergenic

ClinVar germline variants

21 retrieved; paginated sample, class counts are floors:

6 pathogenic, 4 pathogenic/likely pathogenic, 4 uncertain significance, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 conflicting classifications of pathogenicity; risk factor, 1 pathogenic/likely pathogenic; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
162797	NM_004333.6(BRAF):c.1914T>G (p.Asp638Glu)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
222077	NM_004333.6(BRAF):c.1574T>C (p.Leu525Pro)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
182414	NM_058195.4(CDKN2A):c.194-3653G>T	CDKN2A	Pathogenic	criteria provided, multiple submitters, no conflicts
9412	NM_000077.5(CDKN2A):c.301G>T (p.Gly101Trp)	CDKN2A	Pathogenic	criteria provided, multiple submitters, no conflicts
128075	NM_007194.4(CHEK2):c.444+1G>A	CHEK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203023	NM_022552.5(DNMT3A):c.2245C>T (p.Arg749Cys)	DNMT3A	Pathogenic	criteria provided, multiple submitters, no conflicts
42394	NM_000138.5(FBN1):c.5788+5G>A	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
50853	NM_002072.5(GNAQ):c.548G>A (p.Arg183Gln)	GNAQ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29792	NM_001354604.2(MITF):c.1273G>A (p.Glu425Lys)	MITF	Pathogenic/Likely pathogenic; risk factor	criteria provided, multiple submitters, no conflicts
7836	NM_000314.8(PTEN):c.633C>A (p.Cys211Ter)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
192227	NM_000455.5(STK11):c.842del (p.Pro281fs)	STK11	Pathogenic	criteria provided, multiple submitters, no conflicts
2584756	NM_000455.5(STK11):c.140del (p.Gly47fs)	STK11	Likely pathogenic	no assertion criteria provided
2584757	NM_000455.5(STK11):c.431del (p.Pro144fs)	STK11	Likely pathogenic	no assertion criteria provided
2584758	NM_000455.5(STK11):c.667G>T (p.Glu223Ter)	STK11	Likely pathogenic	no assertion criteria provided
13961	NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523315	NM_000059.4(BRCA2):c.2063A>G (p.Tyr688Cys)	BRCA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14307	NM_002386.4(MC1R):c.880G>C (p.Asp294His)	MC1R	Conflicting classifications of pathogenicity; risk factor	criteria provided, conflicting classifications
2498282	NM_004333.6(BRAF):c.1799_1800delinsAC (p.Val600Asp)	BRAF	Uncertain significance	no assertion criteria provided
419802	NM_000077.5(CDKN2A):c.197A>C (p.His66Pro)	CDKN2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
7837	NM_000314.8(PTEN):c.55G>A (p.Asp19Asn)	PTEN	Uncertain significance	criteria provided, multiple submitters, no conflicts
7838	NM_000314.8(PTEN):c.649G>A (p.Val217Ile)	PTEN	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 271 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 3

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
CDKN2A	CDKN2A	GWAS, Orphanet
MC1R	MC1R	GWAS, Orphanet
TERT	TERT	GWAS, Orphanet

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
CDKN2A	LoF	ACYC,BLCA,BRCA,CHOL,COAD,COADREAD,CSCC,EGC,ESCA,ESCC,GBM,HCC,HNSC,LGGNOS,LUAD,LUSC,MEL,MLYM,NPC,NSCLC,OS,PAAD,PANCREAS,RCC,SKCM,SKIN,STAD,STOMACH,WDTC	CIViC #14
BRAF	Act	BLCA,BRCA,CHOL,CLLSLL,COAD,COADREAD,CSCC,DLBCLNOS,GBM,GIST,HGGNOS,LGGNOS,LUAD,MEL,MLYM,NSCLC,OVT,PAST,PCM,PRAD,PRCC,PROSTATE,READ,SACA,SKCM,STAD,UCEC,WDTC	CIViC #5
ATM	LoF	BLCA,BRCA,CCRCC,CHOL,CLLSLL,COAD,COADREAD,ESCA,HCC,LUAD,LUSC,MEL,NSCLC,PAAD,PANCREAS,PANET,PCM,PLMESO,PRAD,PROSTATE,STAD,UCEC,UTUC,WDTC	CIViC #69
PTEN	LoF	ANGS,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,CHRCC,COADREAD,CSCC,ESCA,GB,GBM,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LUAD,LUSC,MBL,MEL,MT,NSCLC,OVT,PANET,PAST,PRAD,PRCC,PROSTATE,RCC,SCLC,SKCM,SOFT_TISSUE,STAD,UCEC,UCS,WDTC	CIViC #41
RNASE1	Act	HNSC,MEL,SKCM	CIViC #4753
RNASE3	Act	BLCA	CIViC #4767
SOX10			CIViC #5418
STAG2	LoF	AML,BLCA,CCRCC,ES,GBM,LUSC,MBL,PAST,PRCC,UCEC,WDTC	CIViC #8553
STAG3			CIViC #8552
TBK1			CIViC #11322
CD44			CIViC #855
CD274	LoF	DLBCLNOS	CIViC #11335
PREX2	Act	BLCA,BRCA,COAD,DLBCLNOS,ESCA,ESCC,HCC,MEL,OVT,PANCREAS,PRAD,STAD	CIViC #15344
CTNNB1	Act	ACC,COAD,COADREAD,ESCA,HCC,LIHB,LUAD,MBL,MEL,NSCLC,OVT,PAST,PRAD,PROSTATE,RMS,SKIN,SOFT_TISSUE,STAD,UCEC,WT	CIViC #1290
CMTR2	LoF	LUAD
ERBB3	Act	BLCA,BRCA,CESC,CHOL,COADREAD,NBL,PRAD,STAD,UCEC,UCS,UTUC	CIViC #1733
ERBB4	LoF	BLCA,BRCA,CCRCC,CHOL,COADREAD,ESCA,HCC,MEL,PRAD,STAD	CIViC #1734
EZH2	Act	ALL,AML,DLBCLNOS,ES,MLYM,NHL	CIViC #63
AKT1	Act	ALL,BRCA,CESC,COADREAD,PRAD,PROSTATE,SARCNOS,UCEC,WDTC	CIViC #2
AKT3	Act	PROSTATE,SKCM	CIViC #7936
MTOR	Act	BLCA,BRCA,CCRCC,CHRCC,CLLSLL,COADREAD,HCC,LGGNOS,PANET,RCC,UCEC	CIViC #2073
ALK	Act	BRCA,HCC,NBL,NSCLC,PROSTATE,SCLC	CIViC #1
GNAS	Act	BRCA,COADREAD,ESCA,HCC,LUAD,MBL,PAAD,PANCREAS	CIViC #2319
IFNGR1			CIViC #2888
JAK2	Act	ALL,AML,BLADDER,BRCA,NSCLC	CIViC #28
KIT	Act	AML,GIST,MEL,MGCT	CIViC #29
KRAS	Act	ALL,AML,ANSC,BLADDER,BLCA,BRCA,CEAD,CESC,CHOL,CLLSLL,COAD,COADREAD,DLBCLNOS,EGC,ESCA,ESCC,HCC,LUAD,LUSC,MEL,MGCT,MT,NSCLC,OVT,PAAD,PANCREAS,PAST,PCM,PRAD,PRCC,READ,STAD,STOMACH,UCEC,UCS,WDTC	CIViC #30
MAP2K1	Act	DLBCLNOS,LUAD,MEL,NSCLC,SKCM	CIViC #31
MERTK			CIViC #8331
NF1	LoF	ACC,ALL,AML,ANGS,BLCA,BRCA,CCRCC,CHOL,CLLSLL,COADREAD,GB,GBM,GIST,HCC,HNSC,LGGNOS,LMS,LUAD,LUNG,LUSC,MEL,NBL,NSCLC,OVT,PAST,PGNG,PLMESO,RMS,SKCM,SOFT_TISSUE,STAD,THYM,UCS	CIViC #3867

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
RB1	Moderate	Autosomal dominant	melanoma	6
CMTR2	Limited	Autosomal dominant	melanoma	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CDKN2A	Orphanet:1333	Familial pancreatic carcinoma
CDKN2A	Orphanet:1501	Adrenocortical carcinoma
CDKN2A	Orphanet:252206	Melanoma and neural system tumor syndrome
CDKN2A	Orphanet:404560	Familial atypical multiple mole melanoma syndrome
CDKN2A	Orphanet:524	Li-Fraumeni syndrome
CDKN2A	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
CDKN2A	Orphanet:618	Familial melanoma
CDKN2A	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
MC1R	Orphanet:618	Familial melanoma
MC1R	Orphanet:79432	Oculocutaneous albinism type 2
ATM	Orphanet:100	Ataxia-telangiectasia
ATM	Orphanet:1331	Familial prostate cancer
ATM	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
ATM	Orphanet:227535	Hereditary breast cancer
ATM	Orphanet:370109	Ataxia-telangiectasia variant
ATM	Orphanet:440437	Familial colorectal cancer Type X
ATM	Orphanet:52416	Mantle cell lymphoma
ATM	Orphanet:67038	B-cell chronic lymphocytic leukemia
PTEN	Orphanet:109	Bannayan-Riley-Ruvalcaba syndrome
PTEN	Orphanet:137608	Segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome
PTEN	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PTEN	Orphanet:201	Cowden syndrome
PTEN	Orphanet:210548	Macrocephaly-intellectual disability-autism syndrome
PTEN	Orphanet:2969	Proteus-like syndrome
PTEN	Orphanet:494547	Squamous cell carcinoma of the hypopharynx
PTEN	Orphanet:494550	Squamous cell carcinoma of the larynx
PTEN	Orphanet:500464	Squamous cell carcinoma of the nasal cavity and paranasal sinuses
PTEN	Orphanet:500478	Squamous cell carcinoma of the oropharynx
PTEN	Orphanet:502363	Squamous cell carcinoma of the oral cavity
PTEN	Orphanet:502366	Squamous cell carcinoma of the lip
PTEN	Orphanet:65285	Lhermitte-Duclos disease
PTEN	Orphanet:79076	Juvenile polyposis of infancy
SOX10	Orphanet:163746	Peripheral demyelinating neuropathy-central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung disease
SOX10	Orphanet:478	Kallmann syndrome
SOX10	Orphanet:895	Waardenburg syndrome type 2
SOX10	Orphanet:897	Waardenburg-Shah syndrome
STAG2	Orphanet:220386	Semilobar holoprosencephaly
STAG2	Orphanet:521258	Xq25 microduplication syndrome
STAG2	Orphanet:93925	Alobar holoprosencephaly

Cohort genes → proteins

75 cohort genes, 74 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	32
gwas_and_clinvar	1
civic_only	29
multi_evidence	13

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CDKN2A	HGNC:1787	ENSG00000147889	P42771	Cyclin-dependent kinase inhibitor 2A	gwas,clinvar,civic_evidence
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	clinvar,civic_evidence
MC1R	HGNC:6929	ENSG00000258839	Q01726	Melanocyte-stimulating hormone receptor	gwas,clinvar
ATM	HGNC:795	ENSG00000149311	Q13315	Serine-protein kinase ATM	gwas,civic_evidence
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	clinvar,civic_evidence
RNASE1	HGNC:10044	ENSG00000129538	P07998	Ribonuclease pancreatic	civic_evidence
RNASE3	HGNC:10046	ENSG00000169397	P12724	Eosinophil cationic protein	civic_evidence
SOX10	HGNC:11190	ENSG00000100146	P56693	Transcription factor SOX-10	civic_evidence
STAG2	HGNC:11355	ENSG00000101972	Q8N3U4	Cohesin subunit SA-2	civic_evidence
STAG3	HGNC:11356	ENSG00000066923	Q9UJ98	Cohesin subunit SA-3	civic_evidence
TBK1	HGNC:11584	ENSG00000183735	Q9UHD2	Serine/threonine-protein kinase TBK1	civic_evidence
CD44	HGNC:1681	ENSG00000026508	P16070	CD44 antigen	civic_evidence
CD274	HGNC:17635	ENSG00000120217	Q9NZQ7	Programmed cell death 1 ligand 1	civic_evidence
PREX2	HGNC:22950	ENSG00000046889	Q70Z35	Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein	civic_evidence
CTNNB1	HGNC:2514	ENSG00000168036	P35222	Catenin beta-1	civic_evidence
CMTR2	HGNC:25635	ENSG00000180917	Q8IYT2	Cap-specific mRNA (nucleoside-2’-O-)-methyltransferase 2	gencc
ERBB3	HGNC:3431	ENSG00000065361	P21860	Receptor tyrosine-protein kinase erbB-3	civic_evidence
ERBB4	HGNC:3432	ENSG00000178568	Q15303	Receptor tyrosine-protein kinase erbB-4	civic_evidence
EZH2	HGNC:3527	ENSG00000106462	Q15910	Histone-lysine N-methyltransferase EZH2	civic_evidence
AKT1	HGNC:391	ENSG00000142208	P31749	RAC-alpha serine/threonine-protein kinase	civic_evidence
AKT3	HGNC:393	ENSG00000117020	Q9Y243	RAC-gamma serine/threonine-protein kinase	civic_evidence
MTOR	HGNC:3942	ENSG00000198793	P42345	Serine/threonine-protein kinase mTOR	civic_evidence
ALK	HGNC:427	ENSG00000171094	Q9UM73	ALK tyrosine kinase receptor	civic_evidence
GNAS	HGNC:4392	ENSG00000087460	O95467	Neuroendocrine secretory protein 55	civic_evidence
IFNGR1	HGNC:5439	ENSG00000027697	P15260	Interferon gamma receptor 1	civic_evidence
JAK2	HGNC:6192	ENSG00000096968	O60674	Tyrosine-protein kinase JAK2	civic_evidence
KIT	HGNC:6342	ENSG00000157404	P10721	Mast/stem cell growth factor receptor Kit	civic_evidence
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	civic_evidence
MAP2K1	HGNC:6840	ENSG00000169032	Q02750	Dual specificity mitogen-activated protein kinase kinase 1	civic_evidence
MERTK	HGNC:7027	ENSG00000153208	Q12866	Tyrosine-protein kinase Mer	civic_evidence
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	civic_evidence
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	civic_evidence
PDGFRA	HGNC:8803	ENSG00000134853	P16234	Platelet-derived growth factor receptor alpha	civic_evidence
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	civic_evidence
PIK3R2	HGNC:8980	ENSG00000105647	O00459	Phosphatidylinositol 3-kinase regulatory subunit beta	civic_evidence
RB1	HGNC:9884	ENSG00000139687	P06400	Retinoblastoma-associated protein	gencc
SETDB1	HGNC:10761	ENSG00000143379	Q15047	Histone-lysine N-methyltransferase SETDB1	gwas
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	clinvar
STK11	HGNC:11389	ENSG00000118046	Q15831	Serine/threonine-protein kinase STK11	clinvar
TAL2	HGNC:11557	ENSG00000186051	Q16559	T-cell acute lymphocytic leukemia protein 2	gwas
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	gwas
TYR	HGNC:12442	ENSG00000077498	P14679	Tyrosinase	gwas
CERS2	HGNC:14076	ENSG00000143418	Q96G23	Ceramide synthase 2	gwas
CASP8	HGNC:1509	ENSG00000064012	Q14790	Caspase-8	gwas
PIGU	HGNC:15791	ENSG00000101464	Q9H490	GPI-anchor transamidase component PIGU	gwas
CCND1	HGNC:1582	ENSG00000110092	P24385	G1/S-specific cyclin-D1	gwas
MYH7B	HGNC:15906	ENSG00000078814	A7E2Y1	Myosin-7B	gwas
RALY	HGNC:15921	ENSG00000125970	Q9UKM9	RNA-binding protein Raly	gwas
SLC45A2	HGNC:16472	ENSG00000164175	Q9UMX9	Membrane-associated transporter protein	gwas
CHEK2	HGNC:16627	ENSG00000183765	O96017	Serine/threonine-protein kinase Chk2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDKN2A	Cyclin-dependent kinase inhibitor 2A	Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6.
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
MC1R	Melanocyte-stimulating hormone receptor	G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha, beta, and gamma-MSH) and adrenocorticotropic hormone/ACTH, which are peptide products of the POMC precursor protein.
ATM	Serine-protein kinase ATM	Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor.
PTEN	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins.
RNASE1	Ribonuclease pancreatic	Endonuclease that catalyzes the cleavage of RNA on the 3’ side of pyrimidine nucleotides.
RNASE3	Eosinophil cationic protein	Cytotoxin and helminthotoxin with low-efficiency ribonuclease activity.
SOX10	Transcription factor SOX-10	Transcription factor that plays a central role in developing and mature glia.
STAG2	Cohesin subunit SA-2	Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication.
STAG3	Cohesin subunit SA-3	Meiosis specific component of cohesin complex.
TBK1	Serine/threonine-protein kinase TBK1	Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents.
CD44	CD44 antigen	Cell-surface receptor that plays a role in cell-cell interactions, cell adhesion and migration, helping them to sense and respond to changes in the tissue microenvironment.
CD274	Programmed cell death 1 ligand 1	Plays a critical role in induction and maintenance of immune tolerance to self.
PREX2	Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein	Functions as a RAC1 guanine nucleotide exchange factor (GEF), activating Rac proteins by exchanging bound GDP for free GTP.
CTNNB1	Catenin beta-1	Key downstream component of the canonical Wnt signaling pathway.
CMTR2	Cap-specific mRNA (nucleoside-2’-O-)-methyltransferase 2	S-adenosyl-L-methionine-dependent methyltransferase that mediates mRNA cap2 2’-O-ribose methylation to the 5’-cap structure of mRNAs.
ERBB3	Receptor tyrosine-protein kinase erbB-3	Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins.
ERBB4	Receptor tyrosine-protein kinase erbB-4	Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell prolife…
EZH2	Histone-lysine N-methyltransferase EZH2	Catalytic subunit of the PRC2/EED-EZH2 complex, a Polycomb group (PcG) complex that methylates ‘Lys-9’ (H3K9me) and ‘Lys-27’ (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene.
AKT1	RAC-alpha serine/threonine-protein kinase	AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis.
AKT3	RAC-gamma serine/threonine-protein kinase	AKT3 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis.
MTOR	Serine/threonine-protein kinase mTOR	Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals.
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.
IFNGR1	Interferon gamma receptor 1	Receptor subunit for interferon gamma/INFG that plays crucial roles in antimicrobial, antiviral, and antitumor responses by activating effector immune cells and enhancing antigen presentation.
JAK2	Tyrosine-protein kinase JAK2	Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications.
KIT	Mast/stem cell growth factor receptor Kit	Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell develo…
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
MAP2K1	Dual specificity mitogen-activated protein kinase kinase 1	Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway.
MERTK	Tyrosine-protein kinase Mer	Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including LGALS3, TUB, TULP1 or GAS6.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
PDGFRA	Platelet-derived growth factor receptor alpha	Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis.
PIK3CA	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.
PIK3R2	Phosphatidylinositol 3-kinase regulatory subunit beta	Regulatory subunit of phosphoinositide-3-kinase (PI3K), a kinase that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3).
RB1	Retinoblastoma-associated protein	Tumor suppressor that is a key regulator of the G1/S transition of the cell cycle.
SETDB1	Histone-lysine N-methyltransferase SETDB1	Histone methyltransferase that specifically trimethylates ‘Lys-9’ of histone H3 (H3K9me3).
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
STK11	Serine/threonine-protein kinase STK11	Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage…
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
TYR	Tyrosinase	This is a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds.
CERS2	Ceramide synthase 2	Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward very-long-chain fatty acyl-CoA (chain length C22-C27).
CASP8	Caspase-8	Thiol protease that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood.
PIGU	GPI-anchor transamidase component PIGU	Component of the glycosylphosphatidylinositol-anchor (GPI-anchor) transamidase (GPI-T) complex that catalyzes the formation of the linkage between a proprotein and a GPI-anchor and participates in GPI anchored protein biosynthesis.
CCND1	G1/S-specific cyclin-D1	Regulatory component of the cyclin D1-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition.
MYH7B	Myosin-7B	Involved in muscle contraction.
RALY	RNA-binding protein Raly	RNA-binding protein that acts as a transcriptional cofactor for cholesterol biosynthetic genes in the liver.
SLC45A2	Membrane-associated transporter protein	Proton-associated glucose and sucrose transporter.
CHEK2	Serine/threonine-protein kinase Chk2	Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks.
CDK10	Cyclin-dependent kinase 10	Cyclin-dependent kinase that phosphorylates the transcription factor ETS2 (in vitro) and positively controls its proteasomal degradation (in cells).
CDKAL1	Threonylcarbamoyladenosine tRNA methylthiotransferase	Catalyzes the methylthiolation of N6-threonylcarbamoyladenosine (t(6)A), leading to the formation of 2-methylthio-N6-threonylcarbamoyladenosine (ms(2)t(6)A) at position 37 in tRNAs that read codons beginning with adenine.

Protein-family classification

Druggable: 35 · Difficult: 10 · Unknown: 30 · Druggable fraction: 0.47

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	19	7.0×	1e-10
Complement	1	3.6×	0.998
Enzyme (other)	8	1.3×	0.998
Antibody/Immunoglobulin	3	1.2×	0.998
Phosphatase	1	1.1×	0.998
Transporter	1	1.0×	0.998
Scaffold/PPI	4	0.9×	0.998
Other/Unknown	30	0.7×	0.998
Transcription factor	6	0.7×	0.998
Protease	1	0.5×	0.998
GPCR	1	0.3×	0.998

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDKN2A	Scaffold/PPI	no		Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor, Tumor_suppres_ARF
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
MC1R	GPCR	yes		GPCR_Rhodpsn, MSH_rcpt, Melcrt_ACTH_rcpt
ATM	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom
RNASE1	Enzyme (other)	yes	4.6.1.18	RNaseA, RNaseA_AS, RNaseA_domain
RNASE3	Other/Unknown	no		RNaseA, RNaseA_AS, RNaseA_domain
SOX10	Transcription factor	no		HMG_box_dom, Sox_N, HMG_box_dom_sf
STAG2	Other/Unknown	no		STAG, ARM-type_fold, SCD
STAG3	Other/Unknown	no		STAG, ARM-type_fold, SCD
TBK1	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, Protein_kinase_ATP_BS
CD44	Other/Unknown	no		Link_dom, CD44_antigen, C-type_lectin-like/link_sf
CD274	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
PREX2	Scaffold/PPI	no		DH_dom, DEP_dom, GDS_CDC24_CS
CTNNB1	Other/Unknown	no		Armadillo, ARM-like, Beta-catenin
CMTR2	Enzyme (other)	yes	2.1.1.296	RNA_MeTrfase_FtsJ_dom, Adrift-typ_MeTrfase, SAM-dependent_MTases_sf
ERBB3	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
ERBB4	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
EZH2	Enzyme (other)	yes	2.1.1.356	SANT/Myb, SET_dom, EZH1/EZH2_N
AKT1	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, PH_domain
AKT3	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, PH_domain
MTOR	Kinase	yes		PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
ALK	Kinase	yes	2.7.10.1	Prot_kinase_dom, MAM_dom, Ser-Thr/Tyr_kinase_cat_dom
GNAS	Other/Unknown	no		NESP55, Gprotein_alpha_S, Gprotein_alpha_su
IFNGR1	Antibody/Immunoglobulin	yes		FN3_dom, Interferon_gamma_rcpt_asu, Ig-like_fold
JAK2	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2
KIT	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
MAP2K1	Kinase	yes	2.7.12.2	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
MERTK	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot
NRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
PDGFRA	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom
PIK3R2	Kinase	yes	2.7.1.137	RhoGAP_dom, SH2, SH3_domain
RB1	Other/Unknown	no		RB_B, RB_A, Cyclin-like_dom
SETDB1	Enzyme (other)	yes	2.1.1.355	SET_dom, Methyl_CpG_DNA-bd, Tudor
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
STK11	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
TAL2	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, TAL-like
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
TYR	Enzyme (other)	yes	1.14.18.1	Tyrosinase_Cu-bd, Di-copper_centre_dom_sf, Tyrosinase/Hemocyanin
CERS2	Transcription factor	no	2.3.1.24	HD, TLC-dom, Homeodomain-like_sf
CASP8	Enzyme (other)	yes	3.4.22.61	Pept_C14_p20, DED_dom, Pept_C14_p10
PIGU	Other/Unknown	no		PIG-U
CCND1	Other/Unknown	no		Cyclin_C-dom, Cyclin_N, Cyclin-like_dom
MYH7B	Scaffold/PPI	no		Myosin_head_motor_dom-like, Myosin_tail, SH3_Myosin
RALY	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, hnRNP_C
SLC45A2	Transporter	yes		MFS, MFS_trans_sf
CHEK2	Kinase	yes	2.7.11.1	FHA_dom, Prot_kinase_dom, Ser/Thr_kinase_AS

Expression context

Cohort genes with no expression data: 0.

69 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)	75
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	12
ganglionic eminence	8
ventricular zone	7
male germ line stem cell (sensu Vertebrata) in testis	7
stromal cell of endometrium	6
colonic epithelium	5
left testis	5
sperm	5
sural nerve	5
secondary oocyte	5
primordial germ cell in gonad	5
right testis	4
adrenal tissue	4
cortical plate	4
epithelium of nasopharynx	4
endothelial cell	3
oocyte	3
visceral pleura	3
ileal mucosa	3
endometrium epithelium	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDKN2A	220	ubiquitous	marker	parotid gland, cervix squamous epithelium, pituitary gland
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
MC1R	180	broad	yes	granulocyte, right uterine tube, left testis
ATM	286	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum
PTEN	256	ubiquitous	marker	sperm, endothelial cell, calcaneal tendon
RNASE1	283	broad	marker	left testis, right testis, right lung
RNASE3	147	tissue_specific	marker	trabecular bone tissue, bone marrow, bone marrow cell
SOX10	218	broad	marker	inferior olivary complex, sural nerve, dorsal motor nucleus of vagus nerve
STAG2	299	ubiquitous	marker	mucosa of paranasal sinus, calcaneal tendon, sural nerve
STAG3	185	broad	marker	oocyte, right testis, left testis
TBK1	284	ubiquitous	marker	colonic epithelium, calcaneal tendon, lateral nuclear group of thalamus
CD44	294	ubiquitous	marker	parotid gland, stromal cell of endometrium, mammalian vulva
CD274	208	ubiquitous	marker	cartilage tissue, placenta, lower lobe of lung
PREX2	241	broad	marker	calcaneal tendon, endothelial cell, visceral pleura
CTNNB1	295	ubiquitous	marker	adrenal tissue, ventricular zone, periodontal ligament
CMTR2	253	ubiquitous	yes	germinal epithelium of ovary, ileal mucosa, jejunal mucosa
ERBB3	274	broad	marker	trigeminal ganglion, jejunal mucosa, dorsal root ganglion
ERBB4	226	broad	marker	endothelial cell, secondary oocyte, cranial nerve II
EZH2	216	ubiquitous	marker	ganglionic eminence, ventricular zone, embryo
AKT1	273	ubiquitous	marker	stromal cell of endometrium, ganglionic eminence, endometrium epithelium
AKT3	231	ubiquitous	marker	cortical plate, calcaneal tendon, embryo
MTOR	207	ubiquitous	marker	primordial germ cell in gonad, right hemisphere of cerebellum, cerebellar hemisphere
ALK	181	broad	marker	sperm, male germ cell, male germ line stem cell (sensu Vertebrata) in testis
GNAS	312	ubiquitous	marker	type B pancreatic cell, postcentral gyrus, Brodmann (1909) area 46
IFNGR1	295	ubiquitous	marker	lower lobe of lung, epithelium of nasopharynx, right lung
JAK2	272	ubiquitous	marker	calcaneal tendon, monocyte, blood vessel layer
KIT	263	broad	marker	lateral nuclear group of thalamus, secondary oocyte, oocyte
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
MAP2K1	298	ubiquitous	marker	secondary oocyte, oocyte, orbitofrontal cortex
MERTK	246	ubiquitous	marker	right adrenal gland cortex, mucosa of stomach, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 106.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AKT1	16,601
CTNNB1	15,668
KRAS	14,509
PTEN	11,626
EZH2	9,646
MTOR	9,490
CDKN2A	9,311
PARP1	8,370
CCND1	8,328
NRAS	7,598

Intra-cohort edges

A	B	Sources
AGR3	CASP8	biogrid_interaction
AKT1	AKT3	biogrid_interaction, intact
AKT1	ATM	intact
AKT1	CCND1	string_interaction
AKT1	MERTK	intact
AKT1	MTOR	intact, string_interaction
AKT1	PIK3CA	biogrid_interaction, string_interaction
AKT1	PTEN	string_interaction
AKT1	SETDB1	intact
AKT1	TBK1	biogrid_interaction
AKT1	TERT	biogrid_interaction
AKT3	BRAF	intact
AKT3	PIK3CA	string_interaction
AKT3	PIK3R2	string_interaction
AKT3	PTEN	string_interaction
ALK	CD274	string_interaction
ALK	KRAS	string_interaction
ALK	NRAS	string_interaction
ARNT	CYP1B1	string_interaction
ATM	BRCA2	string_interaction
ATM	CHEK2	string_interaction
ATM	STK11	string_interaction
BRAF	BRCA2	biogrid_interaction
BRAF	CDKN2A	string_interaction
BRAF	KRAS	biogrid_interaction, intact, string_interaction
BRAF	MAP2K1	biogrid_interaction, intact, string_interaction
BRAF	NF1	string_interaction
BRAF	NRAS	biogrid_interaction, intact, string_interaction
BRAF	PIK3CA	biogrid_interaction, string_interaction
BRAF	PREX2	intact
BRAF	PTEN	biogrid_interaction, string_interaction
BRCA2	CCND1	intact
BRCA2	CHEK2	string_interaction
BRCA2	PARP1	string_interaction
BRCA2	STK11	string_interaction
CASP8	PARP1	biogrid_interaction
CCND1	CDKN2A	biogrid_interaction, string_interaction
CCND1	CTNNB1	string_interaction
CCND1	RB1	string_interaction
CD274	MTOR	biogrid_interaction
CDKAL1	FTO	string_interaction
CDKAL1	NRAS	intact
CDKN2A	KRAS	string_interaction
CDKN2A	MC1R	string_interaction
CDKN2A	RB1	string_interaction
CERS2	GNAS	intact
CLPTM1L	MC1R	string_interaction
CLPTM1L	SLC45A2	string_interaction
CLPTM1L	TERT	string_interaction
CTNNB1	MITF	string_interaction

Structural data

PDB: 57 · AlphaFold-only: 17 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
GNAS	O95467	490
JAK2	O60674	164
MCL1	Q07820	144
PIK3CA	P42336	135
BRAF	P15056	131
PARP1	P09874	106
MAP2K1	Q02750	94
ALK	Q9UM73	79
CD274	Q9NZQ7	76
MTOR	P42345	70
CTSK	P43235	70
KIT	P10721	52
CTNNB1	P35222	50
ARNT	P27540	44
AKT1	P31749	43
DNMT3A	Q9Y6K1	43
MERTK	Q12866	42
EZH2	Q15910	38
CHEK2	O96017	38
GNAQ	P50148	37
CASP8	Q14790	36
NRAS	P01111	35
FTO	Q9C0B1	28
NF1	P21359	26
SETDB1	Q15047	26
TBK1	Q9UHD2	25
ERBB3	P21860	23
TERT	O14746	23
RB1	P06400	19

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACTRT3	Q9BYD9	94.47
ANXA9	O76027	90.51
CERS2	Q96G23	87.31
CDK10	Q15131	86.27
CMTR2	Q8IYT2	86.01
CDKAL1	Q5VV42	82.72
EXOC2	Q96KP1	80.82
TMEM38B	Q9NVV0	80.17
TAL2	Q16559	79.17
CLPTM1L	Q96KA5	78.54
STAG3	Q9UJ98	78.46
SLC45A2	Q9UMX9	77.96
DOCK3	Q8IZD9	75.52
RMDN2	Q96LZ7	74.19
MYH7B	A7E2Y1	73.79
SOX10	P56693	57.32
EYS	Q5T1H1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 728. Enrichment computed across 82 evidence-associated genes (68 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 68 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RAF/MAP kinase cascade	12	10.8×	6e-07	BRAF, ERBB3, ERBB4, JAK2, KIT, KRAS, MAP2K1, NF1 (+4 more)
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	6	45.8×	9e-07	JAK2, KIT, KRAS, NRAS, PIK3CA, PIK3R2
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	5	64.6×	1e-06	KRAS, NRAS, PDGFRA, PIK3CA, PIK3R2
Signaling by PDGFRA extracellular domain mutants	5	64.6×	1e-06	KRAS, NRAS, PDGFRA, PIK3CA, PIK3R2
MITF-M-regulated melanocyte development	9	15.1×	1e-06	CDKN2A, MC1R, SOX10, TERT, CCND1, AKT3, IRF4, KIT (+1 more)
Cytokine Signaling in Immune system	13	7.8×	1e-06	TBK1, CASP8, CCND1, CD44, AKT1, AKT3, IFNGR1, IRF4 (+5 more)
Diseases of signal transduction by growth factor receptors and second messengers	11	9.2×	3e-06	BRAF, AKT1, AKT3, MTOR, ALK, IRF4, JAK2, KIT (+3 more)
Regulation of TP53 Degradation	6	25.8×	9e-06	CDKN2A, ATM, CHEK2, AKT1, AKT3, MTOR
Regulation of TP53 Expression and Degradation	5	38.2×	1e-05	CDKN2A, ATM, AKT1, AKT3, MTOR
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	7	16.6×	1e-05	CTNNB1, AKT1, MTOR, GNAQ, GNAS, PIK3CA, PIK3R2
Signaling by SCF-KIT	6	21.9×	2e-05	JAK2, KIT, KRAS, NRAS, PIK3CA, PIK3R2
Signaling by ERBB2 KD Mutants	5	31.1×	3e-05	ERBB3, ERBB4, KRAS, NRAS, PIK3CA
CD28 dependent PI3K/Akt signaling	5	29.0×	4e-05	AKT1, AKT3, MTOR, PIK3CA, PIK3R2
PIP3 activates AKT signaling	9	8.8×	4e-05	ERBB3, ERBB4, AKT1, AKT3, MTOR, KIT, PDGFRA, PIK3CA (+1 more)
Downstream signal transduction	5	28.0×	4e-05	KRAS, NRAS, PDGFRA, PIK3CA, PIK3R2
Signaling by Interleukins	9	8.5×	5e-05	TBK1, CASP8, CCND1, AKT1, IRF4, JAK2, MAP2K1, MCL1 (+1 more)
FLT3 Signaling	5	25.4×	6e-05	AKT1, AKT3, KRAS, NRAS, PIK3CA
RAF activation	5	24.7×	6e-05	BRAF, JAK2, KRAS, MAP2K1, NRAS
Melanin biosynthesis	3	100.8×	7e-05	TYR, SLC45A2, OCA2
Transcriptional and post-translational regulation of MITF-M expression and activity	6	15.7×	7e-05	MC1R, SOX10, CTNNB1, AKT3, KIT, MITF
Disease	18	3.5×	8e-05	CDKN2A, BRAF, ATM, BRCA2, TBK1, CASP8, CCND1, AKT1 (+10 more)
Cell Cycle	11	5.8×	8e-05	CDKN2A, ATM, BRCA2, STAG2, STAG3, TERT, CCND1, STN1 (+3 more)
Tie2 Signaling	4	35.4×	1e-04	KRAS, NRAS, PIK3CA, PIK3R2
Signaling by RAF1 mutants	5	20.5×	1e-04	BRAF, JAK2, KRAS, MAP2K1, NRAS
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	4	33.6×	1e-04	CDKN2A, CCND1, CTNNB1, MITF
Regulation of MITF-M-dependent genes involved in pigmentation	5	19.5×	1e-04	SOX10, TYR, CTNNB1, IRF4, MITF
Signaling by moderate kinase activity BRAF mutants	5	18.7×	2e-04	BRAF, JAK2, KRAS, MAP2K1, NRAS
Paradoxical activation of RAF signaling by kinase inactive BRAF	5	18.7×	2e-04	BRAF, JAK2, KRAS, MAP2K1, NRAS
Signaling downstream of RAS mutants	5	18.7×	2e-04	BRAF, JAK2, KRAS, MAP2K1, NRAS
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	7	10.0×	2e-04	ERBB3, ERBB4, AKT1, KIT, PDGFRA, PIK3CA, PIK3R2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 78 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein autophosphorylation	9	16.8×	4e-06	ATM, STK11, CHEK2, ERBB4, AKT1, ALK, JAK2, KIT (+1 more)
phosphatidylinositol 3-kinase/protein kinase B signal transduction	7	18.9×	6e-05	PTEN, PREX2, ERBB3, AKT1, NF1, PIK3CA, PIK3R2
melanin biosynthetic process	4	66.5×	1e-04	MC1R, TYR, ASIP, OCA2
anoikis	4	66.5×	1e-04	STK11, AKT1, MTOR, PIK3CA
melanin biosynthetic process from tyrosine	3	162.0×	1e-04	TYR, SLC45A2, OCA2
epidermal growth factor receptor signaling pathway	6	19.1×	1e-04	BRAF, CTNNB1, ERBB3, ERBB4, AKT1, PIK3CA
heart development	9	9.1×	1e-04	ATM, PTEN, TERT, CASP8, ERBB3, ERBB4, FBN1, MAP2K1 (+1 more)
replicative senescence	4	50.8×	2e-04	CDKN2A, ATM, TERT, CHEK2
peptidyl-threonine phosphorylation	4	45.5×	2e-04	STK11, TBK1, CDK10, AKT1
regulation of signal transduction by p53 class mediator	5	24.6×	2e-04	ATM, STK11, CHEK2, AKT1, MTOR
melanocyte differentiation	4	41.1×	3e-04	SOX10, KIT, MITF, OCA2
cytokine-mediated signaling pathway	7	11.7×	3e-04	CD44, CTNNB1, AKT1, IFNGR1, JAK2, KIT, KRAS
thymus development	5	21.6×	4e-04	BRAF, ATM, TYR, CTNNB1, MAP2K1
pigmentation	4	36.0×	4e-04	MC1R, TYR, KIT, NF1
cellular response to insulin stimulus	6	13.1×	5e-04	PARP1, AKT1, MTOR, PIK3CA, PIK3R2, RB1
negative regulation of neuron apoptotic process	7	9.9×	5e-04	BRAF, TERT, CCND1, ERBB3, JAK2, KRAS, PIK3CA
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	8	8.0×	5e-04	ERBB3, ERBB4, MTOR, JAK2, KIT, MERTK, PDGFRA, PIK3CA
positive regulation of neuron apoptotic process	5	17.4×	7e-04	ATM, CASP8, CTNNB1, MCL1, NF1
MAPK cascade	6	11.8×	8e-04	BRAF, CTNNB1, KRAS, MAP2K1, NF1, NRAS
negative regulation of apoptotic process	11	4.9×	9e-04	BRAF, SOX10, CD44, CTNNB1, ERBB3, ERBB4, AKT1, AKT3 (+3 more)
positive regulation of endothelial cell proliferation	5	14.8×	0.001	AKT1, AKT3, ARNT, NF1, NRAS
positive regulation of receptor signaling pathway via JAK-STAT	4	22.2×	0.002	CYP1B1, ERBB4, JAK2, KIT
positive regulation of gene expression	10	5.0×	0.002	BRAF, ATM, SOX10, CTNNB1, ERBB3, AKT1, IFNGR1, KRAS (+2 more)
oligodendrocyte differentiation	4	21.6×	0.002	SOX10, CTNNB1, MTOR, NF1
Ras protein signal transduction	5	13.2×	0.002	CDKN2A, KRAS, NF1, NRAS, RB1
positive regulation of cell migration	8	6.3×	0.002	ATM, CASP8, EZH2, AKT1, JAK2, KIT, MAP2K1, PDGFRA
negative regulation of macroautophagy	3	43.2×	0.002	AKT1, MTOR, PIK3CA
regulation of autophagosome assembly	3	43.2×	0.002	ATM, CHEK2, MTOR
positive regulation of protein localization to nucleus	4	20.1×	0.002	CDKN2A, STK11, PARP1, AKT1
response to estradiol	5	12.7×	0.002	CASP8, CCND1, CTNNB1, DNMT3A, EZH2

Therapeutics

Drugs indicated for this disease

15 approved, 58 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Aldesleukin	Approved (phase 4)
Binimetinib	Approved (phase 4)
Dacarbazine	Approved (phase 4)
Encorafenib	Approved (phase 4)
Hydroxyurea	Approved (phase 4)
INTERFERON ALFA-2B	Approved (phase 4)
Ipilimumab	Approved (phase 4)
Lifileucel	Approved (phase 4)
Nivolumab	Approved (phase 4)
PEGINTERFERON ALFA-2B	Approved (phase 4)
Pembrolizumab	Approved (phase 4)
TECHNETIUM TC 99M SULFUR COLLOID	Approved (phase 4)
Talimogene Laherparepvec	Approved (phase 4)
Tebentafusp	Approved (phase 4)
Vemurafenib	Approved (phase 4)
Aflibercept	Phase 3 (in late-stage trials)
Atezolizumab	Phase 3 (in late-stage trials)
Bempegaldesleukin	Phase 3 (in late-stage trials)
Brenetafusp	Phase 3 (in late-stage trials)
Camrelizumab	Phase 3 (in late-stage trials)
Carboplatin	Phase 3 (in late-stage trials)
Cemiplimab	Phase 3 (in late-stage trials)
Cholecalciferol	Phase 3 (in late-stage trials)
Cisplatin	Phase 3 (in late-stage trials)
Cobimetinib	Phase 3 (in late-stage trials)
Cytarabine	Phase 3 (in late-stage trials)
Dabrafenib	Phase 3 (in late-stage trials)
Elesclomol	Phase 3 (in late-stage trials)
Epacadostat	Phase 3 (in late-stage trials)
Fianlimab	Phase 3 (in late-stage trials)
Filgrastim	Phase 3 (in late-stage trials)
Fludarabine	Phase 3 (in late-stage trials)
Fotemustine	Phase 3 (in late-stage trials)
GP-100 ANTIGEN	Phase 3 (in late-stage trials)
Hyaluronidase (Human Recombinant)	Phase 3 (in late-stage trials)
INTERFERON ALFA-2A	Phase 3 (in late-stage trials)
INTERFERON GAMMA-1B	Phase 3 (in late-stage trials)
Incomplete Freund’S Adjuvant	Phase 3 (in late-stage trials)
Interferon Alfa	Phase 3 (in late-stage trials)
L19IL2	Phase 3 (in late-stage trials)
Lenalidomide	Phase 3 (in late-stage trials)
Lenvatinib	Phase 3 (in late-stage trials)
Linrodostat	Phase 3 (in late-stage trials)
Melphalan	Phase 3 (in late-stage trials)
Naporafenib	Phase 3 (in late-stage trials)
Oblimersen Sodium	Phase 3 (in late-stage trials)
Onamelatucel-L	Phase 3 (in late-stage trials)
PEGINTERFERON ALFA-2A	Phase 3 (in late-stage trials)
Paclitaxel	Phase 3 (in late-stage trials)
Regramostim	Phase 3 (in late-stage trials)
Relatlimab	Phase 3 (in late-stage trials)
Rivoceranib	Phase 3 (in late-stage trials)
Rose Bengal Free Acid	Phase 3 (in late-stage trials)
Sargramostim	Phase 3 (in late-stage trials)
Seviprotimut-L	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)
Sorafenib	Phase 3 (in late-stage trials)
Spartalizumab	Phase 3 (in late-stage trials)
Temozolomide	Phase 3 (in late-stage trials)
Tilsotolimod	Phase 3 (in late-stage trials)
Timolol	Phase 3 (in late-stage trials)
Toripalimab	Phase 3 (in late-stage trials)
Trametinib	Phase 3 (in late-stage trials)
Tranexamic Acid	Phase 3 (in late-stage trials)
Tremelimumab	Phase 3 (in late-stage trials)
Treosulfan	Phase 3 (in late-stage trials)
Tunlametinib	Phase 3 (in late-stage trials)
Tyrosinase	Phase 3 (in late-stage trials)
Velimogene Aliplasmid	Phase 3 (in late-stage trials)
Vibostolimab	Phase 3 (in late-stage trials)
Vinblastine	Phase 3 (in late-stage trials)
Vitespen	Phase 3 (in late-stage trials)
Vusolimogene Oderparepvec	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): ANTINEOPLASTON A10, Abemaciclib, Acetylcysteine, Acitretin, Alectinib, Astuprotimut-R, Axitinib, Balstilimab, Bardoxolone Methyl, Belzupacap Sarotalocan, Betamethasone, Bevacizumab, Bortezomib, Bosentan, Botensilimab, Budesonide, Buparlisib, Cabozantinib, Cadonilimab, Canakinumab, Capmatinib, Carmustine, Catequentinib, Celecoxib, Ceralasertib, Ceritinib, Cilengitide, Dactinomycin, Dasatinib Anhydrous, Decitabine, Denileukin Diftitox, Denosumab, Dexamethasone, Disulfiram, Domvanalimab, Dostarlimab, Durvalumab, Elacytarabine, Enalapril, Endostatin, Ensartinib, Entinostat, Famitinib, Fludarabine Phosphate, Fludrocortisone Acetate, Ganetespib, Gemcitabine, Hyaluronidase, Hydrocortisone, Imatinib, Imiquimod, Infigratinib, Interferon, Interferon Beta, Ixabepilone, Karenitecin, Lapatinib, Leuprolide, Lomustine, Lovastatin, MUROMONAB-CD3, Melatonin, Meprednisone, Metformin, Methylprednisolone, Milademetan, Nilotinib, Ofatumumab, Olaparib, Onfekafusp Alfa, Palbociclib, Patupilone, Pazopanib, Pegfilgrastim, Pelareorep, Pexidartinib, Polidocanol, Prednisolone, Prednisone, Propranolol, Pucotenlimab, Ramucirumab, Regorafenib, Retlirafusp Alfa, Ribociclib, Rintatolimod, Rituximab, Romidepsin, Saracatinib, Sarilumab, Selinexor, Selumetinib, Semaxanib, Sitravatinib, Sunitinib, Talabostat, Talazoparib, Tanespimycin, Temsirolimus, Tesetaxel, Thalidomide, Thymalfasin, Tilsotolimod Sodium, Tiomolibdate Choline, Tipifarnib, Tiragolumab, Tislelizumab, Tocilizumab, Tretinoin, Triamcinolone, Vatalanib, Veliparib, Volociximab, Zimberelimab.

Drug target analysis

Approved (phase 4): 35 · Phase ≥3: 35 · Phased (≥1): 38 · Undrugged: 37

Druggability breadth: 56 of 82 evidence-associated genes (68%) 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
BRAF	VEMURAFENIB
MC1R	BREMELANOTIDE
ATM	AMIODARONE HYDROCHLORIDE
TBK1	MOMELOTINIB
CD274	MOCLOBEMIDE
CTNNB1	DITHIAZANINE IODIDE
ERBB3	MOBOCERTINIB
ERBB4	MOBOCERTINIB
EZH2	TAZEMETOSTAT
AKT1	CAPIVASERTIB
AKT3	CAPIVASERTIB
MTOR	SALMETEROL XINAFOATE
ALK	CERITINIB
JAK2	FEDRATINIB
KIT	PONATINIB
KRAS	VEMURAFENIB
MAP2K1	VEMURAFENIB
MERTK	FEDRATINIB
PDGFRA	PONATINIB
PIK3CA	IDELALISIB
PIK3R2	IDELALISIB
STK11	FEDRATINIB
TERT	BERBERINE
TYR	ASCORBIC ACID
CERS2	FINGOLIMOD
CASP8	PRIMAQUINE PHOSPHATE
CCND1	PALBOCICLIB
CHEK2	NERATINIB
FTO	FLUORESCEIN
CTSK	BOCEPREVIR
TET2	VADADUSTAT
CYP1B1	PAZOPANIB
PARP1	NIRAPARIB
MCL1	VENETOCLAX
MITF	PERHEXILINE MALEATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTOR	164	4
JAK2	100	4
KIT	99	4
PDGFRA	77	4
PIK3CA	67	4
ALK	61	4
MAP2K1	54	4
BRAF	48	4
MERTK	48	4
ERBB4	47	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF, KRAS, MAP2K1
PONATINIB	4	BRAF, JAK2, KIT, PDGFRA
FEDRATINIB	4	ALK, BRAF, ERBB4, JAK2, KIT, MAP2K1
SORAFENIB	4	BRAF, KIT, MAP2K1, MERTK, PDGFRA
DASATINIB ANHYDROUS	4	BRAF, KIT
RUXOLITINIB	4	ALK, BRAF, JAK2, KIT, MAP2K1, TBK1
INFIGRATINIB PHOSPHATE	4	ALK, BRAF, JAK2, KIT, PDGFRA
INFIGRATINIB	4	ALK, BRAF, JAK2, KIT, PDGFRA
REGORAFENIB	4	BRAF, KIT, PDGFRA
DABRAFENIB	4	BRAF, JAK2, KRAS
COBIMETINIB	4	BRAF, MAP2K1
NILOTINIB	4	BRAF, KIT, PDGFRA
ABEMACICLIB	4	BRAF, CCND1
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	ALK, BRAF, CYP1B1, JAK2, KIT, MERTK
DASATINIB	4	BRAF, ERBB3, ERBB4, JAK2, KIT, MAP2K1
ERLOTINIB	4	ALK, BRAF, ERBB3, ERBB4, JAK2, KIT
GEFITINIB	4	BRAF, CHEK2, ERBB3, ERBB4, KIT
IMATINIB	4	BRAF, KIT, PDGFRA
BREMELANOTIDE	4	MC1R
SETMELANOTIDE	4	MC1R
AFAMELANOTIDE	4	MC1R
AMIODARONE HYDROCHLORIDE	4	ATM
FURAZOLIDONE	4	ATM
ESTRADIOL ACETATE	4	ATM
NAFTIFINE HYDROCHLORIDE	4	ATM
METHYSERGIDE MALEATE	4	ATM, MCL1
AMITRIPTYLINE HYDROCHLORIDE	4	ATM
XYLOMETAZOLINE HYDROCHLORIDE	4	ATM

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 30.

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

Symbol	Assays	Type breakdown
KIT	2,305	Binding:2242, ADMET:32, Functional:22, Toxicity:9
PIK3CA	2,034	Binding:2009, ADMET:19, Toxicity:4, Functional:2
JAK2	2,018	Binding:1911, Functional:51, ADMET:48, Unclassified:4, Toxicity:4
AKT1	1,942	Binding:1900, Functional:34, ADMET:7, Toxicity:1
ALK	1,815	Binding:1801, Functional:13, ADMET:1
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
MTOR	1,375	Binding:1335, Functional:37, ADMET:2, Toxicity:1
MAP2K1	1,200	Binding:1150, Functional:47, ADMET:3
PDGFRA	1,172	Binding:1160, Functional:8, ADMET:4
KRAS	861	Binding:829, Functional:32
EZH2	839	Binding:833, Functional:6
PARP1	825	Binding:814, Functional:8, ADMET:3
CHEK2	690	Binding:687, Functional:2, ADMET:1
AKT3	660	Binding:644, Functional:16
ERBB4	591	Binding:579, ADMET:8, Functional:4
CCND1	576	Binding:574, Functional:1, ADMET:1
MCL1	560	Binding:554, Functional:6
CD274	525	Binding:520, Functional:5
TBK1	475	Binding:473, Functional:2
MERTK	443	Binding:442, Functional:1
CYP1B1	408	ADMET:281, Binding:127
TERT	391	Binding:389, Functional:2
CTSK	376	Binding:365, ADMET:5, Toxicity:5, Functional:1
CTNNB1	361	Binding:358, Functional:3
MC1R	319	Functional:164, Binding:155
STK11	244	Binding:244
ATM	240	Binding:233, Functional:5, ADMET:2
TYR	211	Binding:209, ADMET:2
ERBB3	169	Binding:169
FTO	153	Binding:153
DNMT3A	120	Binding:118, ADMET:1, Functional:1
CASP8	116	Binding:106, Functional:10
SETDB1	65	Binding:64, ADMET:1
RB1	59	Binding:59
CDK10	59	Binding:59
PIK3R2	27	Binding:27
GNAQ	27	Binding:27
TET2	24	Binding:24
NRAS	18	Binding:18
RNASE1	17	Binding:16, ADMET:1
ARNT	16	Binding:16
MITF	10	Functional:10
CD44	9	Binding:9
PTEN	8	Binding:8
CERS2	4	Binding:4
IRF4	3	Binding:3
CDKN2A	2	Binding:2
CDKAL1	1	Binding:1
CLPTM1L	1	Binding:1
ANXA9	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
ATM	2.7.11.1	non-specific serine/threonine protein kinase
PTEN	3.1.3.16, 3.1.3.67	protein-serine/threonine phosphatase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase
RNASE1	4.6.1.18	pancreatic ribonuclease
CMTR2	2.1.1.296	methyltransferase cap2
ERBB3	2.7.10.1	receptor protein-tyrosine kinase
ERBB4	2.7.10.1	receptor protein-tyrosine kinase
EZH2	2.1.1.356	[histone H3]-lysine27 N-trimethyltransferase
AKT1	2.7.11.1	non-specific serine/threonine protein kinase
AKT3	2.7.11.1	non-specific serine/threonine protein kinase
ALK	2.7.10.1	receptor protein-tyrosine kinase
JAK2	2.7.10.2	non-specific protein-tyrosine kinase
KIT	2.7.10.1	receptor protein-tyrosine kinase
KRAS	3.6.5.2	small monomeric GTPase
MAP2K1	2.7.12.2	mitogen-activated protein kinase kinase
MERTK	2.7.10.1	receptor protein-tyrosine kinase
PDGFRA	2.7.10.1	receptor protein-tyrosine kinase
PIK3CA	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
PIK3R2	2.7.1.137	phosphatidylinositol 3-kinase
SETDB1	2.1.1.355, 2.1.1.366, 2.1.1.368	[histone H3]-lysine9 N-trimethyltransferase, [histone H3]-N6,N6-dimethyl-lysine9 N-methyltransferase, [histone H3]-lysine9 N-dimethyltransferase
STK11	2.7.11.1	non-specific serine/threonine protein kinase
TYR	1.14.18.1	tyrosinase
CERS2	2.3.1.24, 2.3.1.297	sphingosine N-acyltransferase, very-long-chain ceramide synthase
CASP8	3.4.22.61	caspase-8
CHEK2	2.7.11.1	non-specific serine/threonine protein kinase
CDK10	2.7.11.22	cyclin-dependent kinase
FTO	1.14.11.53	mRNA N6-methyladenine demethylase
CTSK	3.4.22.38	cathepsin K
PARP1	2.4.2.30	NAD+ ADP-ribosyltransferase
DNMT3A	2.1.1.37	DNA (cytosine-5-)-methyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BRAF	1,442
MC1R	319
ATM	240
TBK1	475
CD274	525
CTNNB1	361
ERBB3	169
ERBB4	591
EZH2	839
AKT1	1,942
AKT3	660
MTOR	1,375
ALK	1,815
JAK2	2,018
KIT	2,305
KRAS	861
MAP2K1	1,200
MERTK	443
PDGFRA	1,172
PIK3CA	2,034
STK11	244
TERT	391
TYR	211
CASP8	116
CCND1	576
CHEK2	690
FTO	153
CTSK	376
CYP1B1	408
PARP1	825

Pharmacogenomics

Cohort genes with a PharmGKB record: 75; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

26 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	BRAF, JAK2, KIT, PDGFRA
FEDRATINIB	4	ALK, BRAF, ERBB4, JAK2, KIT, MAP2K1
SORAFENIB	4	BRAF, KIT, MAP2K1, MERTK, PDGFRA
DASATINIB ANHYDROUS	4	BRAF, KIT
RUXOLITINIB	4	ALK, BRAF, JAK2, KIT, MAP2K1, TBK1
INFIGRATINIB PHOSPHATE	4	ALK, BRAF, JAK2, KIT, PDGFRA
INFIGRATINIB	4	ALK, BRAF, JAK2, KIT, PDGFRA
REGORAFENIB	4	BRAF, KIT, PDGFRA
NILOTINIB	4	BRAF, KIT, PDGFRA
ABEMACICLIB	4	BRAF, CCND1
TOVORAFENIB	4	BRAF
PAZOPANIB	4	ALK, BRAF, CYP1B1, JAK2, KIT, MERTK
DASATINIB	4	BRAF, ERBB3, ERBB4, JAK2, KIT, MAP2K1
ERLOTINIB	4	ALK, BRAF, ERBB3, ERBB4, JAK2, KIT
GEFITINIB	4	BRAF, CHEK2, ERBB3, ERBB4, KIT
IMATINIB	4	BRAF, KIT, PDGFRA
BREMELANOTIDE	4	MC1R
SETMELANOTIDE	4	MC1R
AFAMELANOTIDE	4	MC1R
AMIODARONE HYDROCHLORIDE	4	ATM
FURAZOLIDONE	4	ATM
ESTRADIOL ACETATE	4	ATM
NAFTIFINE HYDROCHLORIDE	4	ATM
METHYSERGIDE MALEATE	4	ATM, MCL1
AMITRIPTYLINE HYDROCHLORIDE	4	ATM
XYLOMETAZOLINE HYDROCHLORIDE	4	ATM

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	35	BRAF, MC1R, ATM, TBK1, CD274, CTNNB1, ERBB3, ERBB4, EZH2, AKT1 (+25 more)
B	Phased (≥1) drug, not yet approved	3	NRAS, RB1, CDK10
C	Druggable family + PDB, no drug	5	PTEN, RNASE1, IFNGR1, SETDB1, DNMT3A
D	Druggable family + AlphaFold only, no drug	3	CMTR2, SLC45A2, EXOC2
E	Difficult family or no structure, no drug	29	CDKN2A, RNASE3, SOX10, STAG2, STAG3, CD44, PREX2, GNAS, NF1, BRCA2 (+19 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNMT3A	120	EZH2
PTEN	8	STK11, AKT1
SOX10	0	MITF
PREX2	0	PIK3CA
IFNGR1	0	JAK2
NF1	0	KRAS, BRAF, NRAS
RALY	0	MC1R
SLC45A2	0	TYR, MC1R
CDKAL1	1	FTO
CLPTM1L	1	TERT
CDKN2A	2	—
RNASE1	17	—
RNASE3	0	—
STAG2	0	—
STAG3	0	—
CD44	9	—
CMTR2	0	—
GNAS	0	—
SETDB1	65	—
BRCA2	0	—
TAL2	0	—
PIGU	0	—
MYH7B	0	—
EYS	0	—
ACTRT3	0	—
AGR3	0	—
EXOC2	0	—
TMEM38B	0	—
STN1	0	—
RMDN2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2,417.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	649
PHASE1/PHASE2	285
PHASE3	135
PHASE4	17
PHASE2/PHASE3	14

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02068196	PHASE4	ACTIVE_NOT_RECRUITING	A National Phase IV Study With Ipilimumab for Patients With Advanced Malignant Melanoma.
NCT03340506	PHASE4	RECRUITING	Dabrafenib and/or Trametinib Rollover Study
NCT06785974	PHASE4	NOT_YET_RECRUITING	Statins to Prevent Immune Checkpoint Inhibitor-induced PRogression of AtherosLerosis
NCT07004335	PHASE4	NOT_YET_RECRUITING	Efficacy and Safety of Iparomlimab and Tuvonralimab Injection in Combination With Bevacizumab After Progression on Anti-PD-(L)1 Therapy in Advanced Melanoma: A Prospective, Single-Arm, Exploratory Clinical Study
NCT07405086	PHASE4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT07445022	PHASE4	RECRUITING	RWS of Tunlametinib in NRAS-Mutant Advanced Melanoma
NCT07504796	PHASE4	RECRUITING	ctDNA-guided Addition of Ipilimumab to Patients Receiving Nivolumab and Relatlimab
NCT07574047	PHASE4	NOT_YET_RECRUITING	MELCHRONO: A Prospective Randomized Study Investigating Chrono-immunotherapy for Advanced Melanoma.
NCT00324272	PHASE4	COMPLETED	Post-Operative Drainage Following Lymph Node Dissection
NCT01053819	PHASE4	COMPLETED	Can We Miss Pigmented Lesions in Psoriasis Patients?
NCT01898585	PHASE4	COMPLETED	An Open-Label Study of Zelboraf (Vemurafenib) in Patients With Braf V600 Mutation Positive Metastatic Melanoma
NCT02451488	PHASE4	COMPLETED	Neoadjuvant Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in Cutaneous Stage L-lll Melanoma
NCT03313544	PHASE4	UNKNOWN	Evolution of the Heart Function When Monitoring Immunotherapies Anti-cancerous Inhibiting PD-1
NCT03715205	PHASE4	COMPLETED	Study to Evaluate the Safety of Pembrolizumab in Participants With Unresectable or Metastatic Melanoma or Non-small Cell Lung Cancer in India (MK-3475-593/KEYNOTE-593)
NCT04261179	PHASE4	UNKNOWN	Study Comparing Lymphoseek® vs. Albumin Nanocolloid in Head and Neck, Melanoma and Breast Cancer
NCT05467137	PHASE4	UNKNOWN	Sentinel Lymph Node Detection in Patients With Stage Ib-III Melanoma Using MSOT and ICG
NCT06116461	PHASE4	UNKNOWN	Nivolumab Dose Optimization in Patients With a Complete, Partial or Stable Response
NCT00003641	PHASE3	ACTIVE_NOT_RECRUITING	High-Dose Interferon Alfa in Treating Patients With Stage II or Stage III Melanoma
NCT01223248	PHASE3	ACTIVE_NOT_RECRUITING	Randomized Study Comparing Two Dosing Schedules for Hypofractionated Image-Guided Radiation Therapy
NCT01274338	PHASE3	ACTIVE_NOT_RECRUITING	Ipilimumab or High-Dose Interferon Alfa-2b in Treating Patients With High-Risk Stage III-IV Melanoma That Has Been Removed by Surgery
NCT02224781	PHASE3	ACTIVE_NOT_RECRUITING	Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAFV600 Melanoma
NCT02362594	PHASE3	ACTIVE_NOT_RECRUITING	Study of Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (MK-3475-054/1325-MG/KEYNOTE-054)
NCT02938299	PHASE3	ACTIVE_NOT_RECRUITING	Neoadjuvant L19IL2/L19TNF- Pivotal Study
NCT03470922	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Study of Relatlimab Plus Nivolumab Versus Nivolumab Alone in Participants With Advanced Melanoma
NCT03553836	PHASE3	ACTIVE_NOT_RECRUITING	Safety and Efficacy of Pembrolizumab Compared to Placebo in Resected High-risk Stage II Melanoma (MK-3475-716/KEYNOTE-716)
NCT03567889	PHASE3	RECRUITING	Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C/D Melanoma Patients
NCT03755739	PHASE2/PHASE3	RECRUITING	Trans-Artery/Intra-Tumor Infusion of Checkpoint Inhibitors Plus Chemodrug for Immunotherapy of Advanced Solid Tumors
NCT04099251	PHASE3	ACTIVE_NOT_RECRUITING	Effectiveness Study of Nivolumab Compared to Placebo in Prevention of Recurrent Melanoma After Complete Resection of Stage IIB/C Melanoma
NCT04309409	PHASE3	ACTIVE_NOT_RECRUITING	Adjuvant Nivolumab Treatment in Stage II (IIA, IIB, IIC) High-risk Melanoma
NCT04657991	PHASE3	ACTIVE_NOT_RECRUITING	A Clinical Trial of Three Study Medicines (Encorafenib, Binimetinib, and Pembrolizumab) in Patients With Advanced or Metastatic Melanoma
NCT04949113	PHASE3	ACTIVE_NOT_RECRUITING	Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma
NCT05078047	PHASE3	RECRUITING	Study Comparing the Standard Administration of IO Versus the Same IO Administered Each 3 Months in Patients in Response After 6 Months of Standard IO
NCT05270044	PHASE3	ACTIVE_NOT_RECRUITING	Adjuvant Encorafenib and Binimetinib in High-risk Stage II Melanoma With a BRAF Mutation.
NCT05352672	PHASE3	ACTIVE_NOT_RECRUITING	Clinical Study of Fianlimab in Combination With Cemiplimab Versus Pembrolizumab in Adolescent and Adult Patients With Previously Untreated Unresectable Locally Advanced or Metastatic Melanoma
NCT05522660	PHASE3	RECRUITING	Immunotherapy or Targeted Therapy With or Without Stereotactic Radiosurgery for Patients With Brain Metastases From Melanoma or Non-small Cell Lung Cancer
NCT05549297	PHASE3	RECRUITING	Tebentafusp Regimen Versus Investigator’s Choice in Previously Treated Advanced Melanoma (TEBE-AM)
NCT05608291	PHASE3	ACTIVE_NOT_RECRUITING	A Trial to See if the Combination of Fianlimab With Cemiplimab Works Better Than Pembrolizumab for Preventing or Delaying Melanoma From Coming Back After it Has Been Removed With Surgery
NCT05625399	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Subcutaneous Nivolumab + Relatlimab Fixed-dose Combination (FDC) in Previously Untreated Metastatic or Unresectable Melanoma
NCT05727904	PHASE3	RECRUITING	Study to Investigate Lifileucel Regimen Plus Pembrolizumab Compared With Pembrolizumab Alone in Participants With Untreated Advanced Melanoma.
NCT05732805	PHASE3	ACTIVE_NOT_RECRUITING	A Clinical Study of BCD-217 (Nurulimab + Prolgolimab) Followed by Anti-PD-1 Compared to Anti-PD-1 Monotherapy as First-Line Treatment in Subjects With Unresectable/Metastatic Melanoma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DACARBAZINE	4	33
DABRAFENIB	4	32
VEMURAFENIB	4	32
TRAMETINIB	4	31
IPILIMUMAB	4	25
ALDESLEUKIN	4	20
BINIMETINIB	4	18
COBIMETINIB	4	17
ENCORAFENIB	4	16
RELATLIMAB	4	14
NIVOLUMAB	4	13
SARGRAMOSTIM	4	13
CEMIPLIMAB	4	10
SORAFENIB TOSYLATE	4	9
TALIMOGENE LAHERPAREPVEC	4	9
INTERFERON ALFA-2B	4	7
PEMBROLIZUMAB	4	7
AXITINIB	4	6
SELUMETINIB	4	6
VINBLASTINE	4	6
DENILEUKIN DIFTITOX	4	5
PEGINTERFERON ALFA-2B	4	5
TEMSIROLIMUS	4	5
TREMELIMUMAB	4	5
TRETINOIN	4	5
HYALURONIDASE (HUMAN RECOMBINANT)	4	4
LENVATINIB	4	4
TEBENTAFUSP	4	4
TILMANOCEPT	4	4
DACTINOMYCIN	4	3

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 202 predictive associations from 256 curated evidence items; also 9 prognostic, 3 predisposing, 2 diagnostic.

Molecular subtype	Therapy	Effect	Level	CIViC
BRAF V600E	Dabrafenib	Sensitivity/Response	CIViC A	EID11244 +5
BRAF V600	Cobimetinib + Vemurafenib	Sensitivity/Response	CIViC A	EID6044 +1
BRAF V600	Atezolizumab + Vemurafenib + Cobimetinib	Sensitivity/Response	CIViC A	EID11238
BRAF V600	Encorafenib + Binimetinib	Sensitivity/Response	CIViC A	EID7287
STAT5B Overexpression	Multi-subtype Natural Human Leukocyte Interferon Alpha	Resistance	CIViC A	EID9777
BRAF V600E	Vemurafenib	Sensitivity/Response	CIViC B	EID1398 +14
BRAF V600K	Vemurafenib	Sensitivity/Response	CIViC B	EID1399 +9
BRAF V600E	Trametinib	Sensitivity/Response	CIViC B	EID2135 +2
BRAF V600K	Dabrafenib + Trametinib	Sensitivity/Response	CIViC B	EID6939 +2
BRAF L597	BRAF Inhibitor	Sensitivity/Response	CIViC B	EID7621 +1
BRAF V600	Dabrafenib + Trametinib	Sensitivity/Response	CIViC B	EID6180 +1
BRAF V600E	Dabrafenib + Trametinib	Sensitivity/Response	CIViC B	EID6178 +1
BRAF V600E	Trametinib + Dabrafenib	Sensitivity/Response	CIViC B	EID6938 +1
BRAF V600K	Dabrafenib	Sensitivity/Response	CIViC B	EID2505 +1
CD274 Expression	Nivolumab + Pembrolizumab	Sensitivity/Response	CIViC B	EID704 +1
BRAF G469	BRAF Inhibitor	Sensitivity/Response	CIViC B	EID7623
BRAF G469	BRAF Inhibitor + Mitogen-Activated Protein Kinase Kinase Inhibitor	Sensitivity/Response	CIViC B	EID7634
BRAF K601E	BRAF Inhibitor	Sensitivity/Response	CIViC B	EID7622
BRAF L597	BRAF Inhibitor + Mitogen-Activated Protein Kinase Kinase Inhibitor	Sensitivity/Response	CIViC B	EID7632
BRAF V600	Dabrafenib	Sensitivity/Response	CIViC B	EID1407
BRAF V600	Vemurafenib + Cobimetinib	Sensitivity/Response	CIViC B	EID1422
BRAF V600	Trametinib	Sensitivity/Response	CIViC B	EID1750
BRAF V600	Trametinib + Dabrafenib	Sensitivity/Response	CIViC B	EID93
BRAF V600D	Dabrafenib	Sensitivity/Response	CIViC B	EID94
BRAF V600E	Cobimetinib + Vemurafenib	Sensitivity/Response	CIViC B	EID1421
BRAF V600K	Trametinib	Sensitivity/Response	CIViC B	EID2506
BRAF V600K	Trametinib + Dabrafenib	Sensitivity/Response	CIViC B	EID6179
BRAF V600M	Mitogen-Activated Protein Kinase Kinase Inhibitor + BRAF Inhibitor	Sensitivity/Response	CIViC B	EID7631
BRAF V600R	BRAF Inhibitor	Sensitivity/Response	CIViC B	EID7615
BRAF V600R	Mitogen-Activated Protein Kinase Kinase Inhibitor + BRAF Inhibitor	Sensitivity/Response	CIViC B	EID7628

+172 more predictive associations (showing top 30 by evidence level).