Melanoma

Summary

Melanoma (MONDO:0005105) is a malignant, usually aggressive tumor composed of atypical, neoplastic melanocytes (Mondo). It is an umbrella term covering 15 Mondo subtypes. This page aggregates 75 associated genes (206 GWAS associations across 47 studies; 51 CIViC-evidence somatic drivers; 21 ClinVar predisposition records) and 2,454 registered clinical trials. The dominant Reactome pathway is Diseases of signal transduction by growth factor receptors and second messengers (20 associated genes). Molecularly, BRAF V600E confers sensitivity to Dabrafenib in Melanoma (CIViC Level A); 215 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 (strongest-evidence selection; the list is capped)
• GWAS associations: 206 (top 1% of diseases corpus-wide)
• ClinVar variants: 21
• Clinical trials: 2,454 (top 1% of diseases corpus-wide)
• Approved drugs (ChEMBL indications): 33 — Aldesleukin, Binimetinib, Dacarbazine, +30 more
• Precision-medicine evidence (CIViC): 216 subtype–drug associations
• Druggability snapshot: 31 of 75 cohort genes are drug-illuminated (an approved/clinical drug with curated evidence); 36 functionally characterized but not yet drugged (CDKN2A, PTEN, RNASE1, RNASE3). Atlas-derived.

Clinical features

Clinical description

Mondo: A malignant, usually aggressive tumor composed of atypical, neoplastic melanocytes. Most often, melanomas arise in the skin (cutaneous melanomas) and include the following histologic subtypes: superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, and lentigo maligna melanoma. Cutaneous melanomas may arise from acquired or congenital melanocytic or dysplastic nevi. Melanomas may also arise in other anatomic sites including the gastrointestinal system, eye, urinary tract, and reproductive system. Melanomas frequently metastasize to lymph nodes, liver, lungs, and brain.

MeSH: A malignant neoplasm derived from cells that are capable of forming melanin, which may occur in the skin of any part of the body, in the eye, or, rarely, in the mucous membranes of the genitalia, anus, oral cavity, or other sites. It occurs mostly in adults and may originate de novo or from a pigmented nevus or malignant lentigo. Melanomas frequently metastasize widely, and the regional lymph nodes, liver, lungs, and brain are likely to be involved. The incidence of malignant skin melanomas is rising rapidly in all parts of the world. (Stedman, 25th ed; from Rook et al., Textbook of Dermatology, 4th ed, p2445)

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 · 206 GWAS associations (47 studies) · 2 GenCC gene-disease records · 2,240 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

Sibling subtypes (2): central nervous system melanocytic neoplasm, … (+1 more under melanocytic neoplasm)

Subtypes (15): scrotum melanoma, amelanotic melanoma, epithelioid cell melanoma, malignant breast melanoma, cutaneous melanoma, metastatic melanoma, non-cutaneous melanoma, ocular melanoma, spindle cell melanoma, mixed epithelioid and spindle cell melanoma, familial melanoma, CDK4 linked melanoma, … (+3 more)

Genetics & variants

GWAS landscape

206 GWAS associations across 47 studies. Top hits map to 33 distinct genes (as reported by GWAS).

Top associations by p-value

showing 30 of 206 associations by p-value:

rsID	p-value	Gene	Risk allele	Odds ratio
rs1805007	2e-72	MC1R	T	0.43
rs35026726	4e-61	ZNF276	C	0.65
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	G	0.72
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
chr3:69964940	2e-23		?	1.62
rs74836424	1e-22	ANKRD11	?	1.47
rs4785763	6e-22	AFG3L1P, AFG3L1P	A	1.36
rs17401449	3e-20	SNTA1 - CBFA2T2	A	0.76
chr3:70012226	9e-20		?	1.55
rs35407	2e-19	SLC45A2	A	0.48
rs1204552	3e-19	NORAD	T	0.75
rs1885120	2e-18	MYH7B	C	1.55
rs201131773	3e-17	MTAP	?	1.19
rs401681	7e-16	CLPTM1L	?	1.23

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.
GCST90854241	Dai J	2025	5,462	454,023	Boosting the Power of Rare Variant Association Studies by Imputation Using Large-scale Sequencing Population.
GCST90854242	Dai J	2025	5,462	454,023	Boosting the Power of Rare Variant Association Studies by Imputation Using Large-scale Sequencing Population.
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.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	3
Tier 2: splice/UTR	2
Tier 3: regulatory	0
Tier 4: intronic/intergenic	45

MAF distribution

Bucket	Variants
common (>=0.05)	43
low_freq (0.01-0.05)	4
rare (<0.01)	0
unknown	3

Functional consequences

7 consequence types:

Consequence	Count
intron_variant	35
unknown	4
intergenic_variant	4
missense_variant	3
non_coding_transcript_exon_variant	2
splice_region_variant	1
3_prime_UTR_variant	1

Top variants

showing 30 of 50 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
chr3:69964940							2e-23	Tier 4: intronic/intergenic
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
chr3:70012226							9e-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

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
7836	NM_000314.8(PTEN):c.633C>A (p.Cys211Ter)	PTEN	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
29792	NM_001354604.2(MITF):c.1273G>A (p.Glu425Lys)	MITF	Pathogenic/Likely pathogenic; risk factor	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
128075	NM_007194.4(CHEK2):c.444+1G>A	CHEK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162797	NM_004333.6(BRAF):c.1914T>G (p.Asp638Glu)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
182414	NM_058195.4(CDKN2A):c.194-3653G>T	CDKN2A	Pathogenic	criteria provided, multiple submitters, no conflicts
192227	NM_000455.5(STK11):c.842del (p.Pro281fs)	STK11	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
2203023	NM_022552.5(DNMT3A):c.2245C>T (p.Arg749Cys)	DNMT3A	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
14307	NM_002386.4(MC1R):c.880G>C (p.Asp294His)	MC1R	Conflicting classifications of pathogenicity; risk factor	criteria provided, conflicting classifications
523315	NM_000059.4(BRCA2):c.2063A>G (p.Tyr688Cys)	BRCA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
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
419802	NM_000077.5(CDKN2A):c.197A>C (p.His66Pro)	CDKN2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2498282	NM_004333.6(BRAF):c.1799_1800delinsAC (p.Val600Asp)	BRAF	Uncertain significance	no assertion criteria provided

Pathogenic / likely-pathogenic variants link to their full per-variant reference — ACMG evidence, calibrated predictors, gnomAD frequency — on Sugi Variant.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 267 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 3

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

3 dual-evidence genes:

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

Somatic driver evidence (intOGen + CIViC, cohort fanout)

51 somatic driver genes:

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
BRCA2	LoF	BLCA,BRCA,CESC,CHOL,HCC,HNSC,LUSC,MBL,OVT,PAAD,PRAD,PROSTATE,RCC,VULVA	CIViC #7
SOX10			CIViC #5418
STAG2	LoF	AML,BLCA,CCRCC,ES,GBM,LUSC,MBL,PAST,PRCC,UCEC,WDTC	CIViC #8553
STAG3			CIViC #8552
TBK1			CIViC #11322
TERT	Act	PRCC	CIViC #79
TYR			CIViC #5972
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
MAP2K2			CIViC #4542
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
NRAS	Act	ALL,AML,ANGS,CHOL,CLLSLL,COAD,COADREAD,GBM,HCC,LGGNOS,LUAD,LUSC,MEL,MGCT,NPC,OVT,PCM,PROSTATE,SKCM,THYM,UCEC,WDTC	CIViC #36
PDGFRA	Act	CSCC,GB,GBM,HGGNOS,LGGNOS,LUSC,PAST	CIViC #38
PIK3CA	Act	ACYC,ANGS,ANSC,BCC,BLADDER,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,COAD,COADREAD,EPM,ESCA,ESCC,GB,GBM,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LMS,LUAD,LUSC,MBL,MGCT,NPC,NSCLC,OVT,PAAD,PAST,PLMESO,PRAD,PRCC,PROSTATE,RCC,SACA,SKCM,SOFT_TISSUE,STAD,UCEC,UCS,UTUC,VULVA,WDTC	CIViC #37
PIK3R2			CIViC #4290
PRKDC			CIViC #4529
RB1	LoF	ACC,BLADDER,BLCA,BRCA,CESC,ESCA,GB,GBM,GIST,HCC,HNSC,LGGNOS,LIPO,LMS,LUAD,LUSC,MEL,MT,NSCLC,OS,OVT,PANCREAS,PCM,PRAD,PROSTATE,RBL,SCLC,SKCM,SOFT_TISSUE,STAD,STOMACH,UCEC,UCS	CIViC #4795
SETDB1	Act	BRCA,CLLSLL,COAD,HCC,HNSC,PAAD,PLMESO,UCEC
STK11	LoF	ANSC,CEAD,CESC,CHOL,LUAD,NSCLC,WDTC	CIViC #5534
TAL2	Act	GBM
CASP8	LoF	BCC,BLCA,BRCA,CEAD,CESC,CSCC,HNSC,NHL,NPC,STAD,VULVA	CIViC #761
CCND1	Act	HNSC,PCM,UCEC	CIViC #8
CHEK2	Act	BRCA	CIViC #8950
TET2	LoF	AML,MDS,MLYM,NHL,PCM,RCC,SOFT_TISSUE	CIViC #55
PARP1			CIViC #199
DNMT3A	LoF	AML,BRCA,CCRCC,HCC,LGGNOS,MDS,PCM,PRCC,WDTC	CIViC #18
GNAQ	Act	HCC,NSCLC,SKCM,UM	CIViC #2317
IRF4	Act	CLLSLL,DLBCLNOS,MLYM,NHL,PCM	CIViC #3043

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.

2 cohort genes:

Gene	Classification	Inheritance	Disease	Records
RB1	Moderate	Autosomal dominant	melanoma	6
CMTR2	Limited	Autosomal dominant	melanoma	2

Orphanet rare-disease linkage (cohort genes)

showing 60 of 267 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
BRCA2	Orphanet:1331	Familial prostate cancer
BRCA2	Orphanet:1333	Familial pancreatic carcinoma
BRCA2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA2	Orphanet:178	Chordoma
BRCA2	Orphanet:227535	Hereditary breast cancer
BRCA2	Orphanet:319462	Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations
BRCA2	Orphanet:440437	Familial colorectal cancer Type X
BRCA2	Orphanet:654	Nephroblastoma
BRCA2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA2	Orphanet:694963	Inflammatory breast cancer
BRCA2	Orphanet:70567	Cholangiocarcinoma
BRCA2	Orphanet:84	Fanconi anemia
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

Cohort genes → proteins

75 cohort genes, 74 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	31
gwas_and_clinvar	1
civic_only	31
multi_evidence	12

Cohort genes

showing 60 of 75 cohort genes:

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
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	clinvar
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
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	gwas
TYR	HGNC:12442	ENSG00000077498	P14679	Tyrosinase	gwas
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
STN1	HGNC:26200	ENSG00000107960	Q9H668	CST complex subunit STN1	gwas
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
MAP2K2	HGNC:6842	ENSG00000126934	P36507	Dual specificity mitogen-activated protein kinase kinase 2	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
PRKDC	HGNC:9413	ENSG00000253729	P78527	DNA-dependent protein kinase catalytic subunit	civic_evidence
RB1	HGNC:9884	ENSG00000139687	P06400	Retinoblastoma-associated protein	gencc
SETDB1	HGNC:10761	ENSG00000143379	Q15047	Histone-lysine N-methyltransferase SETDB1	gwas
STK11	HGNC:11389	ENSG00000118046	Q15831	Serine/threonine-protein kinase STK11	clinvar
TAL2	HGNC:11557	ENSG00000186051	Q16559	T-cell acute lymphocytic leukemia protein 2	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
PARD3	HGNC:16051	ENSG00000148498	Q8TEW0	Partitioning defective 3 homolog	gwas
SLC45A2	HGNC:16472	ENSG00000164175	Q9UMX9	Membrane-associated transporter protein	gwas
CHEK2	HGNC:16627	ENSG00000183765	O96017	Serine/threonine-protein kinase Chk2	clinvar
CDK10	HGNC:1770	ENSG00000185324	Q15131	Cyclin-dependent kinase 10	gwas
CDKAL1	HGNC:21050	ENSG00000145996	Q5VV42	Threonylcarbamoyladenosine tRNA methylthiotransferase	gwas
EYS	HGNC:21555	ENSG00000188107	Q5T1H1	Protein eyes shut homolog	gwas
ACTRT3	HGNC:24022	ENSG00000184378	Q9BYD9	Actin-related protein T3	gwas
AGR3	HGNC:24167	ENSG00000173467	Q8TD06	Anterior gradient protein 3	gwas
CLPTM1L	HGNC:24308	ENSG00000049656	Q96KA5	Lipid scramblase CLPTM1L	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

showing 60 of 70 cohort genes:

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.
BRCA2	Breast cancer type 2 susceptibility protein	Tumor suppressor protein that maintains genome stability primarily by repairing damaged DNA through homologous recombination (HR).
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.
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.
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.
STN1	CST complex subunit STN1	Component of the CST complex proposed to act as a specialized replication factor promoting DNA replication under conditions of replication stress or natural replication barriers such as the telomere duplex.
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-membrane spanning protein tyrosine kinase that phosphorylates type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin receptor (MPL/TPOR); or type II receptors including IFN…
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	Signal transducer in the Ras-MAPK signaling pathway that regulates cell proliferation and survival.
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.
MAP2K2	Dual specificity mitogen-activated protein kinase kinase 2	Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases.
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	Signal transducer in the Ras-MAPK signaling pathway that regulates cell proliferation and survival.
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).
PRKDC	DNA-dependent protein kinase catalytic subunit	Serine/threonine-protein kinase that acts as a molecular sensor for DNA damage.
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).
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…
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.
PARD3	Partitioning defective 3 homolog	Adapter protein involved in asymmetrical cell division and cell polarization processes.
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.
EYS	Protein eyes shut homolog	Required to maintain the integrity of photoreceptor cells.
AGR3	Anterior gradient protein 3	Required for calcium-mediated regulation of ciliary beat frequency and mucociliary clearance in the airway.
CLPTM1L	Lipid scramblase CLPTM1L	Scramblase that mediates the translocation of glucosaminylphosphatidylinositol (alpha-D-GlcN-(1-6)-(1,2-diacyl-sn-glycero-3-phospho)-1D-myo-inositol, GlcN-PI) across the endoplasmic reticulum (ER) membrane, from the cytosolic leaflet to th…
FTO	Alpha-ketoglutarate-dependent dioxygenase FTO	RNA demethylase that mediates oxidative demethylation of different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a regulator of fat mass, adipogenesis and energy homeostasis.
EXOC2	Exocyst complex component 2	Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.
CTSK	Cathepsin K	Thiol protease involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling.

Protein-family classification

Druggable: 38 · Difficult: 9 · Unknown: 28 · Druggable fraction: 0.51

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	21	7.8×	1e-12
Complement	1	3.6×	0.898
Enzyme (other)	9	1.4×	0.898
Antibody/Immunoglobulin	3	1.2×	0.977
Scaffold/PPI	5	1.1×	0.977
Phosphatase	1	1.1×	0.977
Transporter	1	1.0×	0.977
Other/Unknown	28	0.7×	1.000
Protease	1	0.5×	1.000
Transcription factor	4	0.4×	1.000
GPCR	1	0.3×	1.000

Per-gene assignment

showing 60 of 75 cohort genes:

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
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
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
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-like
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
STN1	Other/Unknown	no		NA-bd_OB_tRNA, NA-bd_OB-fold, Stn1
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
MAP2K2	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
PRKDC	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
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
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
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
PARD3	Scaffold/PPI	no		PDZ, Par3/HAL_N, PDZ_sf
SLC45A2	Transporter	yes		MFS, MFS_trans_sf
CHEK2	Kinase	yes	2.7.11.1	FHA_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
CDK10	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
CDKAL1	Other/Unknown	no		TRAM_dom, Methylthiotransferase, MiaB-like_arc_euk
EYS	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G
ACTRT3	Other/Unknown	no		Actin, Actin/actin-like_CS, ATPase_NBD
AGR3	Other/Unknown	no		Thioredoxin-like_fold, Thioredoxin-like_sf, AGR/TXD
CLPTM1L	Other/Unknown	no		CLPTM1

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

20 tissues:

Tissue	Cohort genes
calcaneal tendon	11
ganglionic eminence	9
ventricular zone	8
male germ line stem cell (sensu Vertebrata) in testis	7
stromal cell of endometrium	7
left testis	6
secondary oocyte	6
sperm	5
right testis	5
primordial germ cell in gonad	5
colonic epithelium	4
sural nerve	4
adrenal tissue	4
cortical plate	4
epithelium of nasopharynx	4
endothelial cell	3
oocyte	3
ileal mucosa	3
lower esophagus mucosa	3
endometrium epithelium	3

Per-gene tissue summary

showing 60 of 75 cohort genes:

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
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
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
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
TYR	59	tissue_specific	marker	pigmented layer of retina, male germ line stem cell (sensu Vertebrata) in testis, upper leg skin
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
STN1	284	ubiquitous	marker	lower esophagus mucosa, oral cavity, esophagus 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
MAP2K2	291	ubiquitous	marker	mucosa of transverse colon, right testis, left testis
MERTK	246	ubiquitous	marker	right adrenal gland cortex, mucosa of stomach, right adrenal gland
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte
PDGFRA	289	ubiquitous	marker	tibia, decidua, synovial joint
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon
PIK3R2	138	ubiquitous	marker	cortical plate, ganglionic eminence, stromal cell of endometrium
PRKDC	296	ubiquitous	marker	ventricular zone, stromal cell of endometrium, ganglionic eminence
RB1	287	ubiquitous	marker	epithelium of nasopharynx, choroid plexus epithelium, visceral pleura
SETDB1	269	ubiquitous	marker	sural nerve, monocyte, mononuclear cell
STK11	238	ubiquitous	marker	left testis, right testis, hindlimb stylopod muscle
TAL2	138		yes	kidney epithelium, skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii
CERS2	290	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
CASP8	252	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
PIGU	240	ubiquitous	marker	mucosa of transverse colon, ganglionic eminence, ventricular zone
CCND1	280	ubiquitous	marker	endometrium epithelium, stromal cell of endometrium, upper arm skin
MYH7B	195	broad	yes	apex of heart, hindlimb stylopod muscle, heart left ventricle
RALY	294	ubiquitous	marker	ganglionic eminence, granulocyte, ventricular zone
PARD3	278	ubiquitous	marker	cervix squamous epithelium, tongue squamous epithelium, secondary oocyte
SLC45A2	100	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, pigmented layer of retina, primordial germ cell in gonad
CHEK2	183	ubiquitous	marker	primordial germ cell in gonad, lower esophagus mucosa, male germ line stem cell (sensu Vertebrata) in testis
CDK10	286	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, left lobe of thyroid gland
CDKAL1	201	ubiquitous	marker	buccal mucosa cell, calcaneal tendon, ganglionic eminence
EYS	153	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, islet of Langerhans
ACTRT3	162	broad	yes	sperm, left testis, right testis
AGR3	170	tissue_specific	marker	bronchial epithelial cell, bronchus, ileal mucosa
CLPTM1L	255	ubiquitous	marker	ileal mucosa, kidney epithelium, right lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 145.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AKT1	15,314
CTNNB1	14,329
KRAS	12,700
MTOR	12,649
PIK3CA	11,740
PTEN	9,990
PARP1	9,216
EZH2	8,412
CCND1	7,598
CD44	7,046

Intra-cohort edges

showing 60 of 145 intra-cohort edges:

A	B	Sources
AGR3	AKT1	biogrid_interaction
AGR3	CASP8	biogrid_interaction
AKT1	AKT3	biogrid_interaction
AKT1	BRAF	biogrid_interaction
AKT1	CCND1	string_interaction
AKT1	CTNNB1	string_interaction
AKT1	ERBB3	string_interaction
AKT1	KIT	string_interaction
AKT1	KRAS	string_interaction
AKT1	MTOR	biogrid_interaction, string_interaction
AKT1	PIK3CA	biogrid_interaction, string_interaction
AKT1	PIK3R2	string_interaction
AKT1	PREX2	string_interaction
AKT1	PTEN	string_interaction
AKT1	SETDB1	biogrid_interaction
AKT1	STK11	biogrid_interaction
AKT1	TBK1	biogrid_interaction
AKT1	TERT	biogrid_interaction
AKT3	CD44	biogrid_interaction
AKT3	MTOR	string_interaction
AKT3	PIK3CA	string_interaction
AKT3	PIK3R2	string_interaction
AKT3	PTEN	string_interaction
ALK	CD274	string_interaction
ALK	CDKAL1	biogrid_interaction
ALK	KRAS	string_interaction
ALK	NRAS	string_interaction
ALK	PIK3CA	string_interaction
ALK	PIK3R2	biogrid_interaction
ALK	STK11	string_interaction
ATM	BRCA2	string_interaction
ATM	CD274	biogrid_interaction
ATM	CHEK2	biogrid_interaction, string_interaction
ATM	PRKDC	biogrid_interaction
ATM	STK11	string_interaction
ATM	STN1	string_interaction
BRAF	CCND1	string_interaction
BRAF	CDKN2A	string_interaction
BRAF	KRAS	biogrid_interaction, string_interaction
BRAF	MAP2K1	biogrid_interaction
BRAF	MAP2K2	biogrid_interaction
BRAF	MC1R	string_interaction
BRAF	NF1	string_interaction
BRAF	NRAS	biogrid_interaction, string_interaction
BRAF	PIK3CA	string_interaction
BRAF	PTEN	string_interaction
BRCA2	CCND1	biogrid_interaction
BRCA2	CHEK2	biogrid_interaction, string_interaction
BRCA2	PARP1	string_interaction
BRCA2	STK11	string_interaction
BRCA2	TERT	biogrid_interaction
CCND1	CDKN2A	biogrid_interaction, string_interaction
CCND1	CTNNB1	string_interaction
CCND1	RB1	biogrid_interaction, string_interaction
CD274	MTOR	biogrid_interaction
CDKAL1	FTO	string_interaction
CDKAL1	KRAS	biogrid_interaction
CDKN2A	ERBB3	biogrid_interaction
CDKN2A	KRAS	string_interaction
CDKN2A	MC1R	string_interaction

Structural data

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

Cohort genes with PDB structures

30 cohort genes:

Symbol	UniProt	PDB entries
KRAS	P01116	549
GNAS	O95467	214
JAK2	O60674	171
BRAF	P15056	135
PIK3CA	P42336	135
PARP1	P09874	106
MAP2K1	Q02750	99
ALK	Q9UM73	79
CD274	Q9NZQ7	78
MTOR	P42345	73
CTSK	P43235	70
KIT	P10721	65
AKT1	P31749	55
PRKDC	P78527	51
CTNNB1	P35222	50
DNMT3A	Q9Y6K1	47
MERTK	Q12866	42
EZH2	Q15910	41
GNAQ	P50148	40
CHEK2	O96017	38
NRAS	P01111	36
CASP8	Q14790	36
TERT	O14746	32
FTO	Q9C0B1	28
NF1	P21359	26
SETDB1	Q15047	26
TBK1	Q9UHD2	25
ERBB3	P21860	23
IRF4	Q15306	20
PDGFRA	P16234	19

AlphaFold-only cohort genes (by pLDDT)

17 cohort genes:

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

Alliance gene associations

Curated gene–disease associations from the Alliance of Genome Resources (Disease Ontology) — distinct from the cohort above: implicated (causal/mechanistic) vs biomarker (a marker for the disease).

Implicated genes (35): AGER, ASS1, BMP4, BRAF, BRCA2, CAT, CD40, CDKN2A, CTLA4, ERCC2, ERCC5, FAS, FASLG, GSTP1, HLA-DQA1, IL1RN, JUNB, KDM7A, LRP1B, MAPK1, MC1R, NAF1, NFKB1, NFKBIA, NRAS, RNASET2, RTEL1, SPP1, STN1, TERC, TERT, TLR4, TP53, TYR, VDR

Biomarker genes (30): ARPC2, ATRX, BCL2, BCL2L1, BRD2, BRD4, CAV1, CDKN1A, CHI3L1, EHMT2, ELN, ESR1, ESR2, FLT1, GGT1, GPER1, ICAM1, IER2, KDR, KIT, LTA, MITF, NUF2, PPARGC1A, PRAME, RAP1GAP, SETDB1, SOD2, SOX2, VEGFA

Single-cell datasets (CZ CELLxGENE)

2 single-cell RNA-seq datasets in CZ CELLxGENE are annotated with this disease (747,904 cells total) — public datasets whose disease annotations include this condition (some are broad multi-disease atlases, not disease-specific studies).

2 datasets:

Dataset (largest by cell count)	Organism	Cells
A multi-tissue single-cell tumor microenvironment atlas	Homo sapiens	391,963
Integrated cancer cell-specific single-cell RNA-seq datasets of immune checkpoint blockade-treated patients	Homo sapiens	355,941

Source: CZ CELLxGENE Census (CC BY 4.0) — explore at cellxgene.cziscience.com.

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 844. Enrichment computed across 84 evidence-associated genes (71 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 71 annotated cohort genes). Counts and members are kept as ground-truth.

30 pathways by enrichment:

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Diseases of signal transduction by growth factor receptors and second messengers	20	16.0×	3e-16	BRAF, PTEN, CTNNB1, AKT1, AKT3, MTOR, ALK, IRF4 (+12 more)
Disease	32	5.9×	4e-15	CDKN2A, BRAF, ATM, PTEN, BRCA2, TBK1, CASP8, CCND1 (+24 more)
Signal Transduction	34	4.9×	6e-14	BRAF, MC1R, PTEN, STAG2, STK11, TBK1, TERT, CASP8 (+26 more)
Signaling by Receptor Tyrosine Kinases	16	11.6×	6e-11	BRAF, CD274, CTNNB1, DOCK3, AKT1, AKT3, MTOR, ALK (+8 more)
Cytokine Signaling in Immune system	17	9.8×	1e-10	TBK1, CASP8, CCND1, CD44, AKT1, AKT3, IFNGR1, IRF4 (+9 more)
MAPK1/MAPK3 signaling	11	20.3×	6e-10	BRAF, JAK2, KIT, KRAS, MAP2K1, MAP2K2, NF1, NRAS (+3 more)
PI3K/AKT Signaling in Cancer	8	41.5×	1e-09	PTEN, AKT1, AKT3, MTOR, KIT, PDGFRA, PIK3CA, PIK3R2
MITF-M-regulated melanocyte development	11	17.7×	2e-09	CDKN2A, MC1R, SOX10, TERT, TYR, CCND1, CTNNB1, AKT3 (+3 more)
Immune System	25	4.6×	3e-09	PTEN, RNASE3, TBK1, CASP8, CCND1, CD44, CD274, CTNNB1 (+17 more)
MAPK family signaling cascades	11	15.9×	6e-09	BRAF, JAK2, KIT, KRAS, MAP2K1, MAP2K2, NF1, NRAS (+3 more)
RAF/MAP kinase cascade	13	11.2×	8e-09	BRAF, ERBB3, ERBB4, JAK2, KIT, KRAS, MAP2K1, MAP2K2 (+5 more)
PIP3 activates AKT signaling	12	11.3×	4e-08	PTEN, PREX2, ERBB3, ERBB4, EZH2, AKT1, AKT3, MTOR (+4 more)
Gene expression (Transcription)	20	5.0×	7e-08	CDKN2A, ATM, PTEN, SETDB1, STK11, CCND1, CHEK2, CTNNB1 (+12 more)
Signaling by KIT in disease	5	80.4×	1e-07	JAK2, KIT, NRAS, PIK3CA, PIK3R2
Regulation of TP53 Expression and Degradation	6	43.9×	2e-07	CDKN2A, ATM, CHEK2, AKT1, AKT3, MTOR
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	6	43.9×	2e-07	JAK2, KIT, KRAS, NRAS, PIK3CA, PIK3R2
Response of endothelial cells to shear stress	7	29.6×	2e-07	CTNNB1, AKT1, MTOR, GNAQ, GNAS, PIK3CA, PIK3R2
Intracellular signaling by second messengers	10	12.9×	2e-07	PTEN, PREX2, EZH2, AKT1, AKT3, MTOR, KIT, PDGFRA (+2 more)
Negative regulation of the PI3K/AKT network	7	27.5×	2e-07	PTEN, AKT1, AKT3, KIT, PDGFRA, PIK3CA, PIK3R2
Cellular responses to mechanical stimuli	7	25.6×	3e-07	CTNNB1, AKT1, MTOR, GNAQ, GNAS, PIK3CA, PIK3R2
RNA Polymerase II Transcription	17	5.4×	3e-07	CDKN2A, ATM, PTEN, STK11, CCND1, CHEK2, CTNNB1, CTSK (+9 more)
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	5	61.9×	4e-07	KRAS, NRAS, PDGFRA, PIK3CA, PIK3R2
Signaling by PDGFRA extracellular domain mutants	5	61.9×	4e-07	KRAS, NRAS, PDGFRA, PIK3CA, PIK3R2
Signaling by Interleukins	11	9.9×	4e-07	TBK1, CASP8, CCND1, AKT1, IRF4, JAK2, MAP2K1, MCL1 (+3 more)
Regulation of T cell activation by CD28 family	6	35.7×	4e-07	CD274, AKT1, AKT3, MTOR, PIK3CA, PIK3R2
Signaling by RAS mutants	6	35.7×	4e-07	BRAF, JAK2, KRAS, MAP2K1, MAP2K2, NRAS
Oncogenic MAPK signaling	7	24.5×	4e-07	BRAF, JAK2, KRAS, MAP2K1, MAP2K2, NF1, NRAS
Signaling by VEGF	7	21.6×	8e-07	CTNNB1, AKT1, AKT3, MTOR, NRAS, PIK3CA, PIK3R2
Developmental Biology	20	4.1×	1e-06	CDKN2A, MC1R, RNASE1, SOX10, TERT, TYR, CCND1, CD44 (+12 more)
Signaling by ERBB2	6	29.2×	1e-06	ERBB3, ERBB4, AKT1, AKT3, NRAS, PIK3CA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 80 annotated cohort genes). Counts and members are kept as ground-truth.

30 GO terms by enrichment:

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA-templated transcription	13	36.5×	2e-14	CDKN2A, SETDB1, TAL2, CCND1, RALY, CHEK2, CTNNB1, ERBB4 (+5 more)
peptidyl-threonine phosphorylation	5	55.4×	1e-05	STK11, TBK1, CDK10, AKT1, PRKDC
phosphatidylinositol 3-kinase/protein kinase B signal transduction	7	18.4×	3e-05	PTEN, ERBB3, AKT1, MTOR, NF1, PIK3CA, PIK3R2
protein autophosphorylation	8	14.5×	3e-05	ATM, STK11, CHEK2, ERBB4, ALK, JAK2, KIT, PDGFRA
melanin biosynthetic process from tyrosine	3	158.0×	7e-05	TYR, SLC45A2, OCA2
anoikis	4	64.8×	7e-05	STK11, AKT1, MTOR, PIK3CA
cellular response to insulin stimulus	7	14.9×	7e-05	PARP1, AKT1, MTOR, PIK3CA, PIK3R2, PRKDC, RB1
Schwann cell development	4	52.7×	1e-04	ERBB3, MAP2K1, MAP2K2, NF1
epidermal growth factor receptor signaling pathway	6	18.6×	1e-04	BRAF, CTNNB1, ERBB3, ERBB4, AKT1, PIK3CA
replicative senescence	4	49.6×	1e-04	CDKN2A, ATM, TERT, CHEK2
regulation of signal transduction by p53 class mediator	5	23.9×	2e-04	ATM, STK11, CHEK2, AKT1, MTOR
pigmentation	4	35.1×	4e-04	MC1R, TYR, KIT, NF1
ERBB2-ERBB3 signaling pathway	3	63.2×	9e-04	ERBB3, MAP2K1, MAP2K2
telomere maintenance	5	16.7×	9e-04	ATM, TERT, STN1, PARP1, PRKDC
MAPK cascade	6	11.5×	1e-03	BRAF, KRAS, MAP2K1, MAP2K2, NF1, NRAS
negative regulation of apoptotic process	11	4.8×	0.001	BRAF, SOX10, CD44, CTNNB1, ERBB3, ERBB4, AKT1, AKT3 (+3 more)
insulin-like growth factor receptor signaling pathway	4	24.8×	0.001	AKT1, MAP2K1, MAP2K2, PIK3CA
protein phosphorylation	8	6.8×	0.001	BRAF, STK11, TBK1, CHEK2, AKT1, MTOR, MERTK, PRKDC
melanin biosynthetic process	3	48.6×	0.002	MC1R, TYR, OCA2
positive regulation of protein serine/threonine kinase activity	3	48.6×	0.002	EZH2, MAP2K1, MAP2K2
cytokine-mediated signaling pathway	6	9.8×	0.002	CD44, AKT1, IFNGR1, JAK2, KIT, KRAS
negative regulation of macroautophagy	3	42.1×	0.002	AKT1, MTOR, PIK3CA
regulation of autophagosome assembly	3	42.1×	0.002	ATM, CHEK2, MTOR
Ras protein signal transduction	5	12.8×	0.002	CDKN2A, KRAS, NF1, NRAS, RB1
double-strand break repair	5	12.7×	0.002	ATM, BRCA2, CHEK2, PARP1, PRKDC
positive regulation of cell migration	8	6.2×	0.002	ATM, CASP8, EZH2, AKT1, JAK2, KIT, MAP2K1, PDGFRA
response to estradiol	5	12.4×	0.002	CASP8, CCND1, CTNNB1, DNMT3A, EZH2
negative regulation of cGAS/STING signaling pathway	3	39.5×	0.002	PARP1, AKT1, PRKDC
heart development	7	6.9×	0.003	PTEN, TERT, CASP8, ERBB3, ERBB4, FBN1, NF1
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	7	6.9×	0.003	ERBB3, AKT1, MTOR, JAK2, KIT, PDGFRA, PIK3CA

Therapeutics

Drugs indicated or in trials for this disease

33 approved drugs — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	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)
Talimogene Laherparepvec	Approved (phase 4)
Tebentafusp	Approved (phase 4)
Technetium Tc 99M Sulfur Colloid	Approved (phase 4)
Vemurafenib	Approved (phase 4)
Aflibercept	Approved (phase 3)
Atezolizumab	Approved (phase 3)
Carboplatin	Approved (phase 3)
Cemiplimab	Approved (phase 3)
Cisplatin	Approved (phase 3)
Cobimetinib	Approved (phase 3)
Cytarabine	Approved (phase 3)
Dabrafenib	Approved (phase 3)
Lenvatinib	Approved (phase 3)
Melphalan	Approved (phase 3)
Paclitaxel	Approved (phase 3)
Sorafenib	Approved (phase 3)
Temozolomide	Approved (phase 3)
Toripalimab	Approved (phase 3)
Trametinib	Approved (phase 3)
Tremelimumab	Approved (phase 3)
Treosulfan	Approved (phase 3)
Vinblastine	Approved (phase 3)

154 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Bempegaldesleukin	Phase 3
Brenetafusp	Phase 3
Camrelizumab	Phase 3
Cholecalciferol	Phase 3
Elesclomol	Phase 3
Epacadostat	Phase 3
Fianlimab	Phase 3
Filgrastim	Phase 3
Fludarabine	Phase 3
Fotemustine	Phase 3
Gp-100 Antigen	Phase 3
Hyaluronidase (Human Recombinant)	Phase 3
Incomplete Freund’S Adjuvant	Phase 3
Interferon Alfa	Phase 3
Interferon Alfa-2A	Phase 3
Interferon Gamma-1B	Phase 3
L19IL2	Phase 3
Lenalidomide	Phase 3
Linrodostat	Phase 3
Naporafenib	Phase 3
Oblimersen Sodium	Phase 3
Onamelatucel-L	Phase 3
Peginterferon Alfa-2A	Phase 3
Regramostim	Phase 3
Relatlimab	Phase 3
Rivoceranib	Phase 3
Rose Bengal Free Acid	Phase 3
Sargramostim	Phase 3
Seviprotimut-L	Phase 3
Sodium Chloride	Phase 3
Spartalizumab	Phase 3
Tilsotolimod	Phase 3
Timolol	Phase 3
Tranexamic Acid	Phase 3
Tunlametinib	Phase 3
Tyrosinase	Phase 3
Velimogene Aliplasmid	Phase 3
Vibostolimab	Phase 3
Vitespen	Phase 3
Vusolimogene Oderparepvec	Phase 3
Abemaciclib	Phase 2
Acetylcysteine	Phase 2
Acitretin	Phase 2
Alectinib	Phase 2
Antineoplaston A10	Phase 2
Astuprotimut-R	Phase 2
Axitinib	Phase 2
Balstilimab	Phase 2
Bardoxolone Methyl	Phase 2
Belzupacap Sarotalocan	Phase 2
Betamethasone	Phase 2
Bevacizumab	Phase 2
Bortezomib	Phase 2
Bosentan	Phase 2
Botensilimab	Phase 2
Budesonide	Phase 2
Buparlisib	Phase 2
Cabozantinib	Phase 2
Cadonilimab	Phase 2
Canakinumab	Phase 2
Capmatinib	Phase 2
Carmustine	Phase 2
Catequentinib	Phase 2
Celecoxib	Phase 2
Ceralasertib	Phase 2
Ceritinib	Phase 2
Cilengitide	Phase 2
Dactinomycin	Phase 2
Dasatinib Anhydrous	Phase 2
Decitabine	Phase 2
Denileukin Diftitox	Phase 2
Denosumab	Phase 2
Dexamethasone	Phase 2
Disulfiram	Phase 2
Domvanalimab	Phase 2
Dostarlimab	Phase 2
Durvalumab	Phase 2
Elacytarabine	Phase 2
Enalapril	Phase 2
Endostatin	Phase 2
Ensartinib	Phase 2
Entinostat	Phase 2
Famitinib	Phase 2
Fludarabine Phosphate	Phase 2
Fludrocortisone Acetate	Phase 2
Ganetespib	Phase 2
Gemcitabine	Phase 2
Hyaluronidase	Phase 2
Hydrocortisone	Phase 2
Imatinib	Phase 2
Imiquimod	Phase 2
Infigratinib	Phase 2
Interferon	Phase 2
Interferon Beta	Phase 2
Ixabepilone	Phase 2
Karenitecin	Phase 2
Lapatinib	Phase 2
Leuprolide	Phase 2
Lomustine	Phase 2
Lovastatin	Phase 2
MUROMONAB-CD3	Phase 2
Melatonin	Phase 2
Meprednisone	Phase 2
Metformin	Phase 2
Methylprednisolone	Phase 2
Milademetan	Phase 2
Nilotinib	Phase 2
Ofatumumab	Phase 2
Olaparib	Phase 2
Onfekafusp Alfa	Phase 2
Palbociclib	Phase 2
Patupilone	Phase 2
Pazopanib	Phase 2
Pegfilgrastim	Phase 2
Pelareorep	Phase 2
Pexidartinib	Phase 2
Polidocanol	Phase 2
Prednisolone	Phase 2
Prednisone	Phase 2
Propranolol	Phase 2
Pucotenlimab	Phase 2
Ramucirumab	Phase 2
Regorafenib	Phase 2
Retlirafusp Alfa	Phase 2
Ribociclib	Phase 2
Rintatolimod	Phase 2
Rituximab	Phase 2
Romidepsin	Phase 2
Saracatinib	Phase 2
Sarilumab	Phase 2
Selinexor	Phase 2
Selumetinib	Phase 2
Semaxanib	Phase 2
Sitravatinib	Phase 2
Sunitinib	Phase 2
Talabostat	Phase 2
Talazoparib	Phase 2
Tanespimycin	Phase 2
Temsirolimus	Phase 2
Tesetaxel	Phase 2
Thalidomide	Phase 2
Thymalfasin	Phase 2
Tilsotolimod Sodium	Phase 2
Tiomolibdate Choline	Phase 2
Tipifarnib	Phase 2
Tiragolumab	Phase 2
Tislelizumab	Phase 2
Tocilizumab	Phase 2
Tretinoin	Phase 2
Triamcinolone	Phase 2
Vatalanib	Phase 2
Veliparib	Phase 2
Volociximab	Phase 2
Zimberelimab	Phase 2

Mechanistic alignment (indicated drugs × cohort genes)

12 of the 187 drugs indicated for this disease also target a gene in its associated-gene cohort (75 genes) — a mechanistic rationale linking the disease-direct indication to the disease’s genetics. Atlas-derived cross-reference.

Indicated drug	Cohort targets	Genes
Encorafenib	1	BRAF
Vemurafenib	4	BRAF, KRAS, MAP2K1, MAP2K2
Cobimetinib	3	BRAF, MAP2K1, MAP2K2
Dabrafenib	3	BRAF, JAK2, KRAS
Sorafenib	5	BRAF, KIT, MAP2K1, MERTK, PDGFRA
Abemaciclib	2	BRAF, CCND1
Dasatinib Anhydrous	2	BRAF, KIT
Imatinib	3	BRAF, KIT, PDGFRA
Infigratinib	5	ALK, BRAF, JAK2, KIT, PDGFRA
Nilotinib	3	BRAF, KIT, PDGFRA
Pazopanib	7	ALK, BRAF, CYP1B1, JAK2, KIT, MERTK …
Regorafenib	3	BRAF, KIT, PDGFRA

Drug target analysis

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

Druggability breadth: 58 of 84 evidence-associated genes (69%) 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	Dabrafenib
MC1R	Afamelanotide
ATM	Amiodarone Hydrochloride
TBK1	Amlexanox
TERT	Berberine
TYR	Ascorbic Acid
CD274	Moclobemide
CTNNB1	Dithiazanine Iodide
ERBB3	Afatinib
ERBB4	Afatinib
EZH2	Tazemetostat
AKT1	Capivasertib
AKT3	Capivasertib
MTOR	Alpelisib
ALK	Alectinib
JAK2	Baricitinib
KIT	Avapritinib
KRAS	Adagrasib
MAP2K1	Binimetinib
MAP2K2	Binimetinib
MERTK	Axitinib
PDGFRA	Avapritinib
PIK3CA	Alpelisib
PIK3R2	Idelalisib
PRKDC	Idelalisib
STK11	Fedratinib
CERS2	Fingolimod
CASP8	Primaquine Phosphate
CCND1	Abemaciclib
CHEK2	Bosutinib
FTO	Amiloride
CTSK	Boceprevir
TET2	Deferoxamine
CYP1B1	Berberine
PARP1	Niraparib

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
MAP2K2	52	4
BRAF	48	4
MERTK	48	4

Drugs targeting cohort genes

30 drugs:

Molecule	Max phase	Targets in cohort
Dabrafenib	4	BRAF, JAK2, KRAS
Encorafenib	4	BRAF
Regorafenib	4	BRAF, KIT, PDGFRA
Sorafenib	4	BRAF, KIT, MAP2K1, MERTK, PDGFRA
Vemurafenib	4	BRAF, KRAS, MAP2K1, MAP2K2
Abemaciclib	4	BRAF, CCND1
Cobimetinib	4	BRAF, MAP2K1, MAP2K2
Dasatinib	4	BRAF, ERBB3, ERBB4, JAK2, KIT, MAP2K1
Dasatinib Anhydrous	4	BRAF, KIT
Erlotinib	4	ALK, BRAF, ERBB3, ERBB4, JAK2, KIT
Fedratinib	4	ALK, BRAF, ERBB4, JAK2, KIT, MAP2K1
Gefitinib	4	BRAF, CHEK2, ERBB3, ERBB4, KIT
Imatinib	4	BRAF, KIT, PDGFRA
Infigratinib	4	ALK, BRAF, JAK2, KIT, PDGFRA
Infigratinib Phosphate	4	ALK, BRAF, JAK2, KIT, PDGFRA
Nilotinib	4	BRAF, KIT, PDGFRA
Pazopanib	4	ALK, BRAF, CYP1B1, JAK2, KIT, MERTK
Ponatinib	4	BRAF, JAK2, KIT, PDGFRA
Ruxolitinib	4	ALK, BRAF, JAK2, KIT, MAP2K1, MAP2K2
Tovorafenib	4	BRAF
Afamelanotide	4	MC1R
Bremelanotide	4	MC1R
Setmelanotide	4	MC1R
Amiodarone Hydrochloride	4	ATM
Amitriptyline Hydrochloride	4	ATM
Dipyridamole	4	ATM
Dithiazanine Iodide	4	ATM, CTNNB1
Enoximone	4	ATM
Estradiol Acetate	4	ATM
Estradiol Valerate	4	ATM

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 33.

Cohort genes with ChEMBL bioactivity

49 cohort genes 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
MAP2K2	615	Binding:581, Functional:33, ADMET:1
ERBB4	591	Binding:579, ADMET:8, Functional:4
CCND1	576	Binding:574, Functional:1, ADMET:1
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
PRKDC	363	Binding:363
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
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)

33 cohort enzymes:

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
TYR	1.14.18.1	tyrosinase
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
MAP2K2	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
PRKDC	2.7.11.1	non-specific serine/threonine protein 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
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
TET2	1.14.11.80	methylcytosine dioxygenase
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.

33 cohort genes:

Symbol	ChEMBL assays
BRAF	1,442
MC1R	319
ATM	240
TBK1	475
TERT	391
TYR	211
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
MAP2K2	615
MERTK	443
PDGFRA	1,172
PIK3CA	2,034
PRKDC	363
STK11	244
CASP8	116
CCND1	576
CHEK2	690
FTO	153
CTSK	376
CYP1B1	408
PARP1	825
DNMT3A	120

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

25 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.

25 compounds:

Compound	Max phase	Cohort target (bioactivity)
Regorafenib	4	BRAF, KIT, PDGFRA
Sorafenib	4	BRAF, KIT, MAP2K1, MERTK, PDGFRA
Abemaciclib	4	BRAF, CCND1
Dasatinib	4	BRAF, ERBB3, ERBB4, JAK2, KIT, MAP2K1
Erlotinib	4	ALK, BRAF, ERBB3, ERBB4, JAK2, KIT
Fedratinib	4	ALK, BRAF, ERBB4, JAK2, KIT, MAP2K1
Gefitinib	4	BRAF, CHEK2, ERBB3, ERBB4, KIT
Imatinib	4	BRAF, KIT, PDGFRA
Infigratinib	4	ALK, BRAF, JAK2, KIT, PDGFRA
Infigratinib Phosphate	4	ALK, BRAF, JAK2, KIT, PDGFRA
Nilotinib	4	BRAF, KIT, PDGFRA
Pazopanib	4	ALK, BRAF, CYP1B1, JAK2, KIT, MERTK
Ponatinib	4	BRAF, JAK2, KIT, PDGFRA
Ruxolitinib	4	ALK, BRAF, JAK2, KIT, MAP2K1, MAP2K2
Tovorafenib	4	BRAF
Afamelanotide	4	MC1R
Bremelanotide	4	MC1R
Setmelanotide	4	MC1R
Amiodarone Hydrochloride	4	ATM
Amitriptyline Hydrochloride	4	ATM
Dipyridamole	4	ATM
Dithiazanine Iodide	4	ATM, CTNNB1
Enoximone	4	ATM
Estradiol Acetate	4	ATM
Estradiol Valerate	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, TERT, TYR, CD274, CTNNB1, ERBB3, ERBB4 (+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, BRCA2, SOX10, STAG2, STAG3, CD44, PREX2, STN1, GNAS (+19 more)

Undrugged target profiles

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

37 cohort genes:

Symbol	ChEMBL assays	Drugged partners (top 3)
DNMT3A	120	TET2, EZH2
CDKN2A	2	KRAS
PTEN	8	PIK3CA, AKT1, MTOR
PREX2	0	AKT1
NF1	0	BRAF, NRAS
RALY	0	MC1R
SLC45A2	0	TYR, MC1R
CLPTM1L	1	TERT
RNASE1	17	—
RNASE3	0	—
BRCA2	0	—
SOX10	0	—
STAG2	0	—
STAG3	0	—
CD44	9	—
CMTR2	0	—
STN1	0	—
GNAS	0	—
IFNGR1	0	—
SETDB1	65	—
TAL2	0	—
PIGU	0	—
MYH7B	0	—
PARD3	0	—
CDKAL1	1	—
EYS	0	—
ACTRT3	0	—
AGR3	0	—
EXOC2	0	—
TMEM38B	0	—
RMDN2	0	—
DOCK3	0	—
AFG3L1P	0	—
FBN1	0	—
GNAQ	27	—
ANXA9	1	—
IRF4	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2,454.

Phase distribution (across all retrieved trials)

Phase	Trials
Phase 2	649
Phase 1/2	285
Phase 3	136
Phase 4	16
Phase 2/3	14

Top trials by phase / activity

showing 40 of 2,454 trials:

NCT	Phase	Status	Sponsor	Title
NCT02068196	Phase 4	ACTIVE_NOT_RECRUITING	Oslo University Hospital	A National Phase IV Study With Ipilimumab for Patients With Advanced Malignant Melanoma.
NCT03340506	Phase 4	RECRUITING	Novartis Pharmaceuticals	Dabrafenib and/or Trametinib Rollover Study
NCT06785974	Phase 4	NOT_YET_RECRUITING	Erasmus Medical Center	Statins to Prevent Immune Checkpoint Inhibitor-induced PRogression of AtherosLerosis
NCT07004335	Phase 4	NOT_YET_RECRUITING	Hebei Medical University Fourth Hospital	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	Phase 4	RECRUITING	OHSU Knight Cancer Institute	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT07445022	Phase 4	RECRUITING	Fudan University	RWS of Tunlametinib in NRAS-Mutant Advanced Melanoma
NCT07720726	Phase 4	NOT_YET_RECRUITING	Vanderbilt University Medical Center	Impact of Dysport on PMFF Donor Scar
NCT00324272	Phase 4	COMPLETED	Oxford University Hospitals NHS Trust	Post-Operative Drainage Following Lymph Node Dissection
NCT01053819	Phase 4	COMPLETED	University of Alabama at Birmingham	Can We Miss Pigmented Lesions in Psoriasis Patients?
NCT01898585	Phase 4	COMPLETED	Hoffmann-La Roche	An Open-Label Study of Zelboraf (Vemurafenib) in Patients With Braf V600 Mutation Positive Metastatic Melanoma
NCT02451488	Phase 4	COMPLETED	Mayo Clinic	Neoadjuvant Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in Cutaneous Stage L-lll Melanoma
NCT03313544	Phase 4	UNKNOWN	Assistance Publique Hopitaux De Marseille	Evolution of the Heart Function When Monitoring Immunotherapies Anti-cancerous Inhibiting PD-1
NCT03715205	Phase 4	COMPLETED	Merck Sharp & Dohme LLC	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	Phase 4	UNKNOWN	Anna Cruceta	Study Comparing Lymphoseek® vs. Albumin Nanocolloid in Head and Neck, Melanoma and Breast Cancer
NCT05467137	Phase 4	UNKNOWN	University Medical Center Groningen	Sentinel Lymph Node Detection in Patients With Stage Ib-III Melanoma Using MSOT and ICG
NCT06116461	Phase 4	UNKNOWN	Erasmus Medical Center	Nivolumab Dose Optimization in Patients With a Complete, Partial or Stable Response
NCT00003641	Phase 3	ACTIVE_NOT_RECRUITING	ECOG-ACRIN Cancer Research Group	High-Dose Interferon Alfa in Treating Patients With Stage II or Stage III Melanoma
NCT01223248	Phase 3	ACTIVE_NOT_RECRUITING	Memorial Sloan Kettering Cancer Center	Randomized Study Comparing Two Dosing Schedules for Hypofractionated Image-Guided Radiation Therapy
NCT01274338	Phase 3	ACTIVE_NOT_RECRUITING	National Cancer Institute (NCI)	Ipilimumab or High-Dose Interferon Alfa-2b in Treating Patients With High-Risk Stage III-IV Melanoma That Has Been Removed by Surgery
NCT02224781	Phase 3	ACTIVE_NOT_RECRUITING	National Cancer Institute (NCI)	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	Phase 3	ACTIVE_NOT_RECRUITING	Merck Sharp & Dohme LLC	Study of Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-Risk Stage III Melanoma (MK-3475-054/1325-MG/KEYNOTE-054)
NCT02938299	Phase 3	ACTIVE_NOT_RECRUITING	Philogen S.p.A.	Neoadjuvant L19IL2/L19TNF- Pivotal Study
NCT03470922	Phase 2/3	ACTIVE_NOT_RECRUITING	Bristol-Myers Squibb	A Study of Relatlimab Plus Nivolumab Versus Nivolumab Alone in Participants With Advanced Melanoma
NCT03553836	Phase 3	ACTIVE_NOT_RECRUITING	Merck Sharp & Dohme LLC	Safety and Efficacy of Pembrolizumab Compared to Placebo in Resected High-risk Stage II Melanoma (MK-3475-716/KEYNOTE-716)
NCT03567889	Phase 3	RECRUITING	Philogen S.p.A.	Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C/D Melanoma Patients
NCT03755739	Phase 2/3	RECRUITING	Second Affiliated Hospital of Guangzhou Medical University	Trans-Artery/Intra-Tumor Infusion of Checkpoint Inhibitors Plus Chemodrug for Immunotherapy of Advanced Solid Tumors
NCT04099251	Phase 3	ACTIVE_NOT_RECRUITING	Bristol-Myers Squibb	Effectiveness Study of Nivolumab Compared to Placebo in Prevention of Recurrent Melanoma After Complete Resection of Stage IIB/C Melanoma
NCT04309409	Phase 3	ACTIVE_NOT_RECRUITING	University Hospital, Essen	Adjuvant Nivolumab Treatment in Stage II (IIA, IIB, IIC) High-risk Melanoma
NCT04657991	Phase 3	ACTIVE_NOT_RECRUITING	Pfizer	A Clinical Trial of Three Study Medicines (Encorafenib, Binimetinib, and Pembrolizumab) in Patients With Advanced or Metastatic Melanoma
NCT04949113	Phase 3	ACTIVE_NOT_RECRUITING	The Netherlands Cancer Institute	Neoadjuvant Ipilimumab Plus Nivolumab Versus Standard Adjuvant Nivolumab in Macroscopic Stage III Melanoma
NCT05078047	Phase 3	ACTIVE_NOT_RECRUITING	UNICANCER	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	Phase 3	ACTIVE_NOT_RECRUITING	Pierre Fabre Medicament	Adjuvant Encorafenib and Binimetinib in High-risk Stage II Melanoma With a BRAF Mutation.
NCT05352672	Phase 3	ACTIVE_NOT_RECRUITING	Regeneron Pharmaceuticals	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	Phase 3	RECRUITING	ETOP IBCSG Partners Foundation	Immunotherapy or Targeted Therapy With or Without Stereotactic Radiosurgery for Patients With Brain Metastases From Melanoma or Non-small Cell Lung Cancer
NCT05549297	Phase 3	RECRUITING	Immunocore Ltd	Tebentafusp Regimen Versus Investigator’s Choice in Previously Treated Advanced Melanoma (TEBE-AM)
NCT05608291	Phase 3	ACTIVE_NOT_RECRUITING	Regeneron Pharmaceuticals	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	Phase 3	ACTIVE_NOT_RECRUITING	Bristol-Myers Squibb	A Study of Subcutaneous Nivolumab + Relatlimab Fixed-dose Combination (FDC) in Previously Untreated Metastatic or Unresectable Melanoma
NCT05727904	Phase 3	RECRUITING	Iovance Biotherapeutics, Inc.	Study to Investigate Lifileucel Regimen Plus Pembrolizumab Compared With Pembrolizumab Alone in Participants With Untreated Advanced Melanoma.
NCT05732805	Phase 3	ACTIVE_NOT_RECRUITING	Biocad	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
NCT05751928	Phase 3	ACTIVE_NOT_RECRUITING	Biocad	A Study of Neoadjuvant Therapy With BCD-217 (Nurulimab + Prolgolimab) in Patients With Resectable Stage III Skin Melanoma

Drugs tested across these trials

30 drugs:

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	13
Sargramostim	4	13
Nivolumab	4	12
Cemiplimab	4	10
Sorafenib Tosylate	4	9
Talimogene Laherparepvec	4	9
Interferon Alfa-2B	4	7
Pembrolizumab	4	7
Axitinib	4	6
Dasatinib Anhydrous	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

Other drugs named in trials

Drugs named in these trials’ interventions but not in the ChEMBL table above — includes investigational drugs not yet in ChEMBL. Linked where an Atlas drug page exists.

30 drugs named in trials:

Drug	Max trial phase
Abobotulinumtoxin-A	Phase 4
Atorvastatin	Phase 4
Blood Samples	Phase 4
Etanercept	Phase 4
Fibrin Sealant (Tisseel) used in the Experimental Arm.	Phase 4
Gm-Csf	Phase 4
Immune Checkpoint Inhibitor	Phase 4
Iparomlimab and Tuvonralimab Injection plus Bevacizumab	Phase 4
Lymphoseek	Phase 4
Nanocoll	Phase 4
Tunlametinib	Phase 4
Zelboraf	Phase 4
ABI-007	Phase 3
Abp 206	Phase 3
Adjuvant nivolumab	Phase 3
Adjuvant therapy	Phase 3
Aldesleukin (IL-2)	Phase 3
Allovectin-7	Phase 3
Allovectin-7/dacarbazine	Phase 3
Anti-PD1	Phase 3
Atezolizumab	Phase 3
Autologous Dendritic Cell-Tumor Cell Immunotherapy (DC-TC)	Phase 3
Autologous PBMCs in GM-CSF (MC)	Phase 3
BCD-100	Phase 3
BCD-201	Phase 3
BCD-217	Phase 3
BCD-263	Phase 3
BMS-936558 (Nivolumab)	Phase 3
BMS-986205	Phase 3
Bempegaldesleukin	Phase 3

Precision-medicine subtype map (CIViC)

Drug × molecular subtype, from 272 curated evidence items; also 12 oncogenic, 11 prognostic, 3 predisposing, 2 diagnostic. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

showing 30 of 216 predictive associations by evidence level:

Molecular subtype	Therapy	Effect	Level	CIViC
BRAF V600E	Dabrafenib	Sensitivity/Response	CIViC A	EID11244 +5
BRAF V600	Encorafenib + Binimetinib	Sensitivity/Response	CIViC A	EID7287 +2
BRAF V600	Vemurafenib + Cobimetinib	Sensitivity/Response	CIViC A	EID6044 +2
BRAF V600	Vemurafenib + Cobimetinib + Atezolizumab	Sensitivity/Response	CIViC A	EID13046 +1
BRAF V600	Vemurafenib + Atezolizumab + Cobimetinib	Sensitivity/Response	CIViC A	EID11238
BRAF V600E	Cobimetinib + Vemurafenib + Atezolizumab	Sensitivity/Response	CIViC A	EID13045
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 V600E	Trametinib + Dabrafenib	Sensitivity/Response	CIViC B	EID6938 +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 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	Mitogen-Activated Protein Kinase Kinase Inhibitor + BRAF 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	Atezolizumab + Cobimetinib + Vemurafenib	Sensitivity/Response	CIViC B	EID13044
BRAF V600	Dabrafenib	Sensitivity/Response	CIViC B	EID1407
BRAF V600	Trametinib	Sensitivity/Response	CIViC B	EID1750
BRAF V600D	Dabrafenib	Sensitivity/Response	CIViC B	EID94
BRAF V600E	Vemurafenib + Cobimetinib	Sensitivity/Response	CIViC B	EID1421
BRAF V600E	Dabrafenib + Trametinib	Sensitivity/Response	CIViC B	EID6178
BRAF V600E OR BRAF V600K	Vemurafenib	Sensitivity/Response	CIViC B	EID1410
BRAF V600E OR BRAF V600K	Trametinib + Dabrafenib	Sensitivity/Response	CIViC B	EID93
BRAF V600K	Binimetinib + Encorafenib	Sensitivity/Response	CIViC B	EID13185
BRAF V600K	Trametinib	Sensitivity/Response	CIViC B	EID2506

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