Clear cell renal carcinoma

Summary

Clear cell renal carcinoma (MONDO:0005005) is a cancer with 11 cohort genes (78 GWAS associations across 4 studies; 8 CIViC-evidence somatic drivers; 6 ClinVar predisposition records) and 253 clinical trials. The dominant Reactome pathway is RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (3 cohort genes). Molecularly, PBRM1 Mutation confers sensitivity to CTLA-4 Inhibitor + Anti-PD-L1 Monoclonal Antibody in Clear Cell Renal Cell Carcinoma (CIViC Level B); 7 further subtype–drug associations are mapped below. Top therapeutic interventions include sorafenib, axitinib, and cabozantinib.

At a glance

• Classification: Cancer
• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 11
• GWAS associations: 78
• ClinVar variants: 6
• Clinical trials: 253
• Precision-medicine evidence (CIViC): 8 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	1.99	Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	clear cell renal carcinoma
Mondo ID	MONDO:0005005
EFO	EFO:0000349
Orphanet	319276
DOID	DOID:4467
NCIT	C4033
SNOMED CT	254915003
UMLS	C0279702
MedGen	76018
GARD	0009574
Anatomy (UBERON)	UBERON:0002113
Is cancer (heuristic)	yes

Also known as: clear cell adenocarcinoma of kidney · clear cell adenocarcinoma of the kidney · clear cell adenocarcinoma, kidney · clear cell carcinoma of kidney · clear cell carcinoma of the kidney · clear cell renal cell cancer · clear cell renal cell carcinoma · clear-cell metastatic renal cell carcinoma · conventional (clear cell) renal cell adenocarcinoma · conventional (clear cell) renal cell carcinoma · conventional renal cell carcinoma · Grawitz tumor · Grawitz tumour · hypernephroma · kidney clear cell adenocarcinoma · kidney clear cell carcinoma · RCC, clear cell adenocarcinoma · renal cell carcinoma, clear cell adenocarcinoma · renal clear cell adenocarcinoma · renal clear cell carcinoma

Data availability: 6 ClinVar variants · 78 GWAS associations (4 studies) · 235 cell lines · 46 intOGen driver records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › carcinoma › adenocarcinoma › clear cell adenocarcinoma › clear cell renal carcinoma

Related subtypes (10): hepatocellular clear cell carcinoma, fallopian tube clear cell adenocarcinoma, bladder clear cell adenocarcinoma, urethra clear cell adenocarcinoma, glycogen-rich clear cell breast carcinoma, extrahepatic bile duct clear cell adenocarcinoma, ovarian clear cell adenocarcinoma, cervical clear cell adenocarcinoma, endometrial clear cell adenocarcinoma, hidradenocarcinoma

Subtypes (2): multilocular clear cell renal cell carcinoma, hereditary clear cell renal cell carcinoma

Genetics & variants

GWAS landscape

78 GWAS associations across 4 studies. Top hits map to 33 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs7118554	5e-67	LINC02956 - LINC02953	C	0.62
rs4903064	9e-54	DPF3	C	1.27
rs6470589	1e-33	PVT1	G	1.18
rs4963975	1e-33	SSPN-AS1, SSPN	A	1.2
rs1868089	2e-31	EPAS1	T	1.17
rs11263432	2e-28	LINC02953 - LINC02952	C	0.85
rs11125068	7e-27	EPAS1	G	0.86
rs7629500	1e-23	VHL	A	2.72
rs4765623	3e-23	SCARB1	T	1.15
rs28970524	7e-21	MAD1L1	T	1.16
rs4980572	8e-21	MYEOV - LINC02956	A	0.87
rs3905137	3e-20	MTND4P24 - DCAF12L1	T	0.9
rs61758556	2e-19	AKT1	T	0.83
rs2251636	2e-19	PMF1-BGLAP, PMF1	C	1.13
rs10792035	1e-18	MYEOV	G	0.88
rs4140952	5e-18	DPF3	G	1.13
rs179784	2e-16	KCNQ1	A	0.89
rs55735727	9e-15	ACTRT3 - MYNN	T	0.87
rs6574106	3e-14	DPF3 - DCAF4	C	1.12
rs3807306	1e-13	IRF5	T	0.91
rs2255039	3e-13	MYO7B	C	0.9
rs139729777	3e-13	FANCD2	G	1.14
rs56200772	3e-13	GRB10	G	0.83
rs117706999	4e-13	EXPH5	A	1.38
rs2277283	1e-12	INCENP	C	1.11
rs6916760	3e-12	GMDS	T	0.91
rs12887451	4e-12	ADSS1	G	0.91
rs2950790	5e-12	TEX41	A	0.9
rs12118203	7e-12	PIGR - FCAMR	C	0.9
rs11709427	8e-12	SFMBT1	T	1.1

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90320055	Purdue MP	2024	0	0	Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions.
GCST90320058	Purdue MP	2024	0	0	Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions.
GCST90320061	Purdue MP	2024	0	0	Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions.
GCST90320064	Purdue MP	2024	0	0	Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	1
Tier 3: regulatory	2
Tier 4: intronic/intergenic	46

MAF distribution

Bucket	Variants
common (>=0.05)	48
low_freq (0.01-0.05)	2
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	36
intergenic_variant	10
regulatory_region_variant	2
3_prime_UTR_variant	1
missense_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs7118554	11	69424886	T>C	0.13	intergenic_variant	LINC02956 - LINC02953	5e-67	Tier 4: intronic/intergenic
rs4903064	14	72812712	T>C	0.23	intron_variant	DPF3	9e-54	Tier 4: intronic/intergenic
rs6470589	8	127877126	C>A,G	0.46	intron_variant	PVT1	1e-33	Tier 4: intronic/intergenic
rs4963975	12	26290097	G>A,C	0.26	intron_variant	SSPN-AS1, SSPN	1e-33	Tier 4: intronic/intergenic
rs1868089	2	46327507	C>A,G,T	0.46	intron_variant	EPAS1	2e-31	Tier 4: intronic/intergenic
rs11263432	11	69432586	T>A,C,G	0.38	regulatory_region_variant	LINC02953 - LINC02952	2e-28	Tier 3: regulatory
rs11125068	2	46300677	A>G,T	0.41	intron_variant	EPAS1	7e-27	Tier 4: intronic/intergenic
rs7629500	3	10150788	G>A	0.08	3_prime_UTR_variant	VHL	1e-23	Tier 2: splice/UTR
rs4765623	12	124836304	C>A,T	0.35	intron_variant	SCARB1	3e-23	Tier 4: intronic/intergenic
rs28970524	7	1887848	C>A,G,T	0.38	intron_variant	MAD1L1	7e-21	Tier 4: intronic/intergenic
rs4980572	11	69379851	G>A,C,T	0.41	intergenic_variant	MYEOV - LINC02956	8e-21	Tier 4: intronic/intergenic
rs3905137	X	126491977	G>T	0.38	intergenic_variant	MTND4P24 - DCAF12L1	3e-20	Tier 4: intronic/intergenic
rs61758556	14	104790238	A>T	0.15	intron_variant	AKT1	2e-19	Tier 4: intronic/intergenic
rs2251636	1	156233018	G>A,C	0.38	intron_variant	PMF1-BGLAP, PMF1	2e-19	Tier 4: intronic/intergenic
rs10792035	11	69306340	A>C,G,T	0.38	intron_variant	MYEOV	1e-18	Tier 4: intronic/intergenic
rs4140952	14	72828118	A>G	0.42	intron_variant	DPF3	5e-18	Tier 4: intronic/intergenic
rs179784	11	2760594	G>A	0.48	intron_variant	KCNQ1	2e-16	Tier 4: intronic/intergenic
rs55735727	3	169770360	A>C,G,T	0.25	intron_variant	ACTRT3 - MYNN	9e-15	Tier 4: intronic/intergenic
rs6574106	14	72918958	T>C	0.26	intergenic_variant	DPF3 - DCAF4	3e-14	Tier 4: intronic/intergenic
rs3807306	7	128940626	G>A,C,T	0.48	intron_variant	IRF5	1e-13	Tier 4: intronic/intergenic
rs2255039	2	127637183	T>A,C,G	0.43	intron_variant	MYO7B	3e-13	Tier 4: intronic/intergenic
rs139729777	3	10044399	A>G	0.18	intron_variant	FANCD2	3e-13	Tier 4: intronic/intergenic
rs56200772	7	50676250	C>G	0.11	intron_variant	GRB10	3e-13	Tier 4: intronic/intergenic
rs117706999	11	108536216	G>A	0.02	intron_variant	EXPH5	4e-13	Tier 4: intronic/intergenic
rs2277283	11	62140968	T>A,C,G	0.31	missense_variant	INCENP	1e-12	Tier 1: coding
rs6916760	6	1746787	C>T	0.49	intron_variant	GMDS	3e-12	Tier 4: intronic/intergenic
rs12887451	14	104725689	C>G	0.42	intron_variant	ADSS1	4e-12	Tier 4: intronic/intergenic
rs2950790	2	145002154	G>A,C,T	0.25	intron_variant	TEX41	5e-12	Tier 4: intronic/intergenic
rs12118203	1	206951048	T>C	0.27	intergenic_variant	PIGR - FCAMR	7e-12	Tier 4: intronic/intergenic
rs11709427	3	53034026	C>A,G,T	0.41	intron_variant	SFMBT1	8e-12	Tier 4: intronic/intergenic

ClinVar germline variants

6 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 benign, 1 pathogenic/likely pathogenic, 1 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
233403	NM_000051.4(ATM):c.9019G>T (p.Glu3007Ter)	ATM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14927	NM_000545.8(HNF1A):c.872dup (p.Gly292fs)	HNF1A	Pathogenic	reviewed by expert panel
218955	NM_001405607.1(PBRM1):c.4043_4050del (p.Asp1348fs)	PBRM1	Pathogenic	no assertion criteria provided
861467	NM_004656.4(BAP1):c.535C>T (p.Arg179Trp)	BAP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7602	NM_002542.6(OGG1):c.137G>A (p.Arg46Gln)	OGG1	Uncertain significance	criteria provided, single submitter
14948	NM_000545.8(HNF1A):c.92G>A (p.Gly31Asp)	HNF1A	Benign	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 40 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
PBRM1	LoF	CCRCC,CEAD,CHOL,COADREAD,ESCA,GBC,LUAD,MEL,NSCLC,PLMESO,PRCC,RCC,SKCM,STAD,UCEC	CIViC #62
RNF2	LoF	BRCA,CCRCC,CESC,CHOL,ESCA,HCC,PANCREAS,PLMESO,PRCC,RCC,SACA,SKCM,STAD,UM	CIViC #70
ARID1A	LoF	BL,BLCA,BRCA,CCRCC,CESC,CHOL,CLLSLL,COAD,COADREAD,DLBCLNOS,EGC,ESCA,ESCC,GBC,GBM,HCC,LGGNOS,LUAD,LUNG,LUSC,MBL,MLYM,MT,NHL,NSCLC,OS,OVT,PAAD,PANCREAS,PAST,PRAD,RCC,SCLC,SKIN,STAD,UCEC,UCS,UTUC	CIViC #6559
VHL	LoF	CCRCC,PGNG,RCC	CIViC #58
MTOR	Act	BLCA,BRCA,CCRCC,CHRCC,CLLSLL,COADREAD,HCC,LGGNOS,PANET,RCC,UCEC	CIViC #2073
GNAS	Act	BRCA,COADREAD,ESCA,HCC,LUAD,MBL,PAAD,PANCREAS	CIViC #2319
HNF1A	LoF	HCC,PRCC
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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PBRM1	Orphanet:404511	Clear cell papillary renal cell carcinoma
RNF2	Orphanet:528084	Non-specific syndromic intellectual disability
ARID1A	Orphanet:1465	Coffin-Siris syndrome
VHL	Orphanet:238557	Chuvash erythrocytosis
VHL	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
VHL	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
VHL	Orphanet:892	Von Hippel-Lindau disease
MTOR	Orphanet:269001	Isolated focal cortical dysplasia type IIa
MTOR	Orphanet:269008	Isolated focal cortical dysplasia type IIb
MTOR	Orphanet:457485	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome
MTOR	Orphanet:99802	Hemimegalencephaly
GNAS	Orphanet:189427	Cushing syndrome due to bilateral macronodular adrenocortical disease
GNAS	Orphanet:2762	Progressive osseous heteroplasia
GNAS	Orphanet:562	McCune-Albright syndrome
GNAS	Orphanet:57782	Mazabraud syndrome
GNAS	Orphanet:79443	Pseudohypoparathyroidism type 1A
GNAS	Orphanet:79444	Pseudohypoparathyroidism type 1C
GNAS	Orphanet:79445	Pseudopseudohypoparathyroidism
GNAS	Orphanet:93276	Polyostotic fibrous dysplasia
GNAS	Orphanet:93277	Monostotic fibrous dysplasia
GNAS	Orphanet:94089	Pseudohypoparathyroidism type 1B
HNF1A	Orphanet:319303	Chromophobe renal cell carcinoma
HNF1A	Orphanet:324575	Hyperinsulinism due to HNF1A deficiency
HNF1A	Orphanet:404511	Clear cell papillary renal cell carcinoma
HNF1A	Orphanet:552	MODY
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
OGG1	Orphanet:422526	Hereditary clear cell renal cell carcinoma
BAP1	Orphanet:2495	Meningioma
BAP1	Orphanet:289539	BAP1-related tumor predisposition syndrome
BAP1	Orphanet:39044	Uveal melanoma
BAP1	Orphanet:50251	Pleural mesothelioma
BAP1	Orphanet:528084	Non-specific syndromic intellectual disability
BAP1	Orphanet:618	Familial melanoma

Cohort genes → proteins

11 cohort genes, 11 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	5
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PBRM1	HGNC:30064	ENSG00000163939	Q86U86	Protein polybromo-1	clinvar,civic_evidence
RNF2	HGNC:10061	ENSG00000121481	Q99496	E3 ubiquitin-protein ligase RING2	civic_evidence
ARID1A	HGNC:11110	ENSG00000117713	O14497	AT-rich interactive domain-containing protein 1A	civic_evidence
VHL	HGNC:12687	ENSG00000134086	P40337	von Hippel-Lindau disease tumor suppressor	civic_evidence
MTOR	HGNC:3942	ENSG00000198793	P42345	Serine/threonine-protein kinase mTOR	civic_evidence
GNAS	HGNC:4392	ENSG00000087460	O95467	Neuroendocrine secretory protein 55	civic_evidence
HNF1A	HGNC:11621	ENSG00000135100	P20823	Hepatocyte nuclear factor 1-alpha	clinvar
ATM	HGNC:795	ENSG00000149311	Q13315	Serine-protein kinase ATM	clinvar
OGG1	HGNC:8125	ENSG00000114026	O15527	N-glycosylase/DNA lyase	clinvar
MAGI1	HGNC:946	ENSG00000151276	Q96QZ7	Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1	clinvar
BAP1	HGNC:950	ENSG00000163930	Q92560	Ubiquitin carboxyl-terminal hydrolase BAP1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PBRM1	Protein polybromo-1	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
RNF2	E3 ubiquitin-protein ligase RING2	E3 ubiquitin-protein ligase that mediates monoubiquitination of ‘Lys-119’ of histone H2A (H2AK119Ub), thereby playing a central role in histone code and gene regulation.
ARID1A	AT-rich interactive domain-containing protein 1A	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
VHL	von Hippel-Lindau disease tumor suppressor	Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex.
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.
HNF1A	Hepatocyte nuclear factor 1-alpha	Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver.
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.
OGG1	N-glycosylase/DNA lyase	DNA repair enzyme that incises DNA at 8-oxoG residues.
MAGI1	Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1	Plays a role in coupling actin fibers to cell junctions in endothelial cells, via its interaction with AMOTL2 and CDH5.
BAP1	Ubiquitin carboxyl-terminal hydrolase BAP1	Deubiquitinating enzyme that plays a key role in chromatin by mediating deubiquitination of histone H2A and HCFC1.

Protein-family classification

Druggable: 6 · Difficult: 2 · Unknown: 3 · Druggable fraction: 0.55

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	3	7.6×	0.031
Protease	1	3.3×	0.438
Enzyme (other)	2	2.2×	0.438
Transcription factor	2	1.5×	0.490
Other/Unknown	3	0.5×	0.987

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PBRM1	Other/Unknown	no		BAH_dom, Bromodomain, HMG_box_dom
RNF2	Transcription factor	no	2.3.2.27	Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
ARID1A	Other/Unknown	no		ARID_dom, ARM-like, ARM-type_fold
VHL	Enzyme (other)	yes	2.3.2.B13	VHL_tumour_suppress_b/a_dom, VHL_alpha_dom, VHL_beta_dom
MTOR	Kinase	yes		PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
GNAS	Other/Unknown	no		NESP55, Gprotein_alpha_S, Gprotein_alpha_su
HNF1A	Transcription factor	no		HD, HNF1b_C, HNF1a_C
ATM	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
OGG1	Enzyme (other)	yes	3.2.2.23	HhH-GPD_domain, Ogg1, DNA_glycosylase
MAGI1	Kinase	yes		WW_dom, PDZ, Guanylate_kin-like_dom
BAP1	Protease	yes	3.4.19.12	Peptidase_C12_UCH, Peptidase_C12_UCH_sf, Papain-like_cys_pep_sf

Expression context

Cohort genes with no expression data: 0.

10 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)	11
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	4
ganglionic eminence	3
ventricular zone	3
primordial germ cell in gonad	2
corpus callosum	2
amniotic fluid	1
bone marrow cell	1
embryo	1
monocyte	1
mononuclear cell	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
Brodmann (1909) area 46	1
postcentral gyrus	1
type B pancreatic cell	1
liver	1
mucosa of transverse colon	1
right lobe of liver	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PBRM1	289	ubiquitous	marker	cortical plate, ganglionic eminence, amniotic fluid
RNF2	178	ubiquitous	marker	primordial germ cell in gonad, cortical plate, ganglionic eminence
ARID1A	286	ubiquitous	marker	bone marrow cell, ventricular zone, embryo
VHL	186	ubiquitous	marker	cortical plate, monocyte, mononuclear cell
MTOR	207	ubiquitous	marker	primordial germ cell in gonad, right hemisphere of cerebellum, cerebellar hemisphere
GNAS	312	ubiquitous	marker	type B pancreatic cell, postcentral gyrus, Brodmann (1909) area 46
HNF1A	81	tissue_specific	yes	right lobe of liver, mucosa of transverse colon, liver
ATM	286	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum
OGG1	288	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
MAGI1	133	ubiquitous	marker	ventricular zone, sural nerve, corpus callosum
BAP1	253	ubiquitous	marker	left testis, right testis, right frontal lobe

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTOR	9,490
ATM	7,383
RNF2	3,814
PBRM1	3,540
VHL	3,522
ARID1A	3,476
BAP1	3,373
HNF1A	2,491
MAGI1	2,043
GNAS	410

Intra-cohort edges

A	B	Sources
ARID1A	PBRM1	string_interaction
BAP1	PBRM1	string_interaction
PBRM1	VHL	biogrid_interaction

Structural data

PDB: 11 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAS	O95467	490
VHL	P40337	142
MTOR	P42345	70
OGG1	O15527	47
PBRM1	Q86U86	30
MAGI1	Q96QZ7	16
RNF2	Q99496	15
ATM	Q13315	14
ARID1A	O14497	7
HNF1A	P20823	6
BAP1	Q92560	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 147. Enrichment computed across 11 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	3	90.2×	6e-04	PBRM1, RNF2, ARID1A
Regulation of TP53 Expression and Degradation	2	103.8×	0.009	MTOR, ATM
DNA Double Strand Break Response	2	95.2×	0.009	ATM, BAP1
Cellular response to heat stress	2	78.8×	0.010	MTOR, ATM
Defective OGG1 Substrate Binding	1	1142.0×	0.014	OGG1
Defective OGG1 Substrate Processing	1	1142.0×	0.014	OGG1
Defective OGG1 Localization	1	1142.0×	0.014	OGG1
Regulation of TP53 Degradation	2	58.6×	0.014	MTOR, ATM
DNA Double-Strand Break Repair	2	49.6×	0.014	ATM, BAP1
Regulation of PTEN gene transcription	2	35.7×	0.020	RNF2, MTOR
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	2	32.2×	0.021	MTOR, GNAS
Autophagy	2	29.7×	0.021	MTOR, ATM
RMTs methylate histone arginines	2	29.3×	0.021	PBRM1, ARID1A
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	2	29.3×	0.021	ATM, BAP1
Regulation of TP53 Activity	2	26.6×	0.024	MTOR, ATM
Replication of the SARS-CoV-1 genome	1	285.5×	0.029	VHL
Replication of the SARS-CoV-2 genome	1	285.5×	0.029	VHL
Macroautophagy	2	23.1×	0.029	MTOR, ATM
DNA Repair	2	19.7×	0.034	ATM, BAP1
Sensing of DNA Double Strand Breaks	1	190.3×	0.039	ATM
APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway	1	163.1×	0.043	OGG1
RHOBTB3 ATPase cycle	1	114.2×	0.054	VHL
Displacement of DNA glycosylase by APEX1	1	103.8×	0.054	OGG1
TP53 Regulates Transcription of Caspase Activators and Caspases	1	95.2×	0.054	ATM
Pexophagy	1	95.2×	0.054	ATM
Defective homologous recombination repair (HRR) due to PALB2 loss of function	1	95.2×	0.054	ATM
Positive Regulation of CDH1 Gene Transcription	1	95.2×	0.054	ARID1A
Transcriptional Regulation by TP53	2	12.4×	0.054	MTOR, ATM
RNA Polymerase II Transcription	3	6.8×	0.054	ARID1A, MTOR, ATM
Diseases of DNA Double-Strand Break Repair	1	81.6×	0.055	ATM

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of double-strand break repair	3	93.8×	1e-03	PBRM1, ARID1A, ATM
positive regulation of cell differentiation	3	73.0×	0.001	PBRM1, ARID1A, VHL
regulation of autophagosome assembly	2	204.3×	0.003	MTOR, ATM
regulation of cellular response to heat	2	191.5×	0.003	MTOR, ATM
mitotic cell cycle	3	36.5×	0.003	PBRM1, RNF2, BAP1
vascular endothelial cell response to laminar fluid shear stress	2	133.2×	0.004	MTOR, GNAS
regulation of G0 to G1 transition	2	122.6×	0.004	PBRM1, ARID1A
regulation of nucleotide-excision repair	2	109.4×	0.005	PBRM1, ARID1A
regulation of mitotic metaphase/anaphase transition	2	90.1×	0.006	PBRM1, ARID1A
germ cell development	2	82.8×	0.006	RNF2, MTOR
positive regulation of T cell differentiation	2	82.8×	0.006	PBRM1, ARID1A
cellular response to reactive oxygen species	2	74.7×	0.007	ATM, OGG1
regulation of signal transduction by p53 class mediator	2	69.6×	0.007	MTOR, ATM
positive regulation of myoblast differentiation	2	66.6×	0.007	PBRM1, ARID1A
chromatin remodeling	3	19.9×	0.007	PBRM1, RNF2, ARID1A
thrombocyte differentiation	1	1532.0×	0.008	BAP1
nucleate erythrocyte differentiation	1	1532.0×	0.008	BAP1
positive regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process	1	1532.0×	0.008	MTOR
negative regulation of double-strand break repair via single-strand annealing	1	1532.0×	0.008	OGG1
negative regulation of TORC1 signaling	2	58.9×	0.008	VHL, ATM
regulation of G1/S transition of mitotic cell cycle	2	55.7×	0.008	PBRM1, ARID1A
protein stabilization	3	18.2×	0.008	VHL, MTOR, ATM
negative regulation of autophagy	2	47.1×	0.009	VHL, MTOR
DNA damage response	3	14.6×	0.010	MTOR, ATM, OGG1
leukocyte proliferation	1	766.0×	0.010	BAP1
establishment of RNA localization to telomere	1	766.0×	0.010	ATM
establishment of protein-containing complex localization to telomere	1	766.0×	0.010	ATM
regulation of locomotor rhythm	1	766.0×	0.010	MTOR
positive regulation of cytoplasmic translational initiation	1	766.0×	0.010	MTOR
positive regulation of telomerase catalytic core complex assembly	1	766.0×	0.010	ATM

Therapeutics

Drugs indicated for this disease

9 approved, 12 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Axitinib	Approved (phase 4)
Belzutifan	Approved (phase 4)
Bevacizumab	Approved (phase 4)
Everolimus	Approved (phase 4)
Ipilimumab	Approved (phase 4)
Nivolumab	Approved (phase 4)
Pembrolizumab	Approved (phase 4)
Sunitinib	Approved (phase 4)
Temsirolimus	Approved (phase 4)
Aldesleukin	Phase 3 (in late-stage trials)
Avelumab	Phase 3 (in late-stage trials)
Cabozantinib	Phase 3 (in late-stage trials)
Dovitinib	Phase 3 (in late-stage trials)
Durvalumab	Phase 3 (in late-stage trials)
Girentuximab	Phase 3 (in late-stage trials)
Hyaluronidase (Human Recombinant)	Phase 3 (in late-stage trials)
Interferon Alfa	Phase 3 (in late-stage trials)
Lenvatinib	Phase 3 (in late-stage trials)
Pazopanib	Phase 3 (in late-stage trials)
Tremelimumab	Phase 3 (in late-stage trials)
Zanzalintinib	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Ascorbic Acid, Camrelizumab, Carotuximab, Catequentinib, Entinostat, Fludarabine, INTERFERON ALFA-2B, Ivuxolimab, Ixabepilone, Palbociclib, Panobinostat, Sintilimab, Sitravatinib, Tislelizumab, Vandetanib, Vorinostat.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 7

Druggability breadth: 11 of 11 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

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

Symbol	Example approved molecule
VHL	OSIMERTINIB
MTOR	SALMETEROL XINAFOATE
ATM	AMIODARONE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTOR	164	4
ATM	35	4
VHL	7	4
PBRM1	2	2
RNF2	0	0
ARID1A	0	0
GNAS	0	0
HNF1A	0	0
OGG1	0	0
MAGI1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OSIMERTINIB	4	VHL
BRIGATINIB	4	VHL
CRIZOTINIB	4	VHL
ADAGRASIB	4	VHL
SALMETEROL XINAFOATE	4	MTOR
IMIPRAMINE	4	MTOR
AMOXAPINE	4	MTOR
IDARUBICIN	4	MTOR
TETRABENAZINE	4	MTOR
TEMSIROLIMUS	4	MTOR
MIFEPRISTONE	4	MTOR
ZIPRASIDONE HYDROCHLORIDE	4	MTOR
PIMOZIDE	4	MTOR
NAFTOPIDIL	4	MTOR
NICLOSAMIDE	4	MTOR
FELODIPINE	4	MTOR
NICARDIPINE	4	MTOR
AZACITIDINE	4	MTOR
TRIFLUPERIDOL	4	MTOR
CYCLOSPORINE	4	MTOR
CLEMASTINE	4	MTOR
TERFENADINE	4	MTOR
FLUOROURACIL	4	MTOR
PANCURONIUM	4	MTOR
EVEROLIMUS	4	MTOR
NIFEDIPINE	4	MTOR
PRAZOSIN	4	MTOR
MAPROTILINE	4	MTOR
DOMPERIDONE	4	MTOR
ALPELISIB	4	MTOR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
VHL	3,575	Binding:3482, Functional:54, ADMET:39
MTOR	1,375	Binding:1335, Functional:37, ADMET:2, Toxicity:1
ATM	240	Binding:233, Functional:5, ADMET:2
PBRM1	193	Binding:193
OGG1	19	Binding:18, Functional:1
RNF2	16	Binding:16
ARID1A	6	Binding:6
BAP1	5	Binding:4, Functional:1
MAGI1	4	Binding:4
HNF1A	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNF2	2.3.2.27	RING-type E3 ubiquitin transferase
VHL	2.3.2.B13
ATM	2.7.11.1	non-specific serine/threonine protein kinase
OGG1	3.2.2.23, 4.2.99.18	DNA-formamidopyrimidine glycosylase, DNA-(apurinic or apyrimidinic site) lyase
BAP1	3.4.19.12	ubiquitinyl hydrolase 1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PBRM1	193
VHL	3,575
MTOR	1,375
ATM	240

Pharmacogenomics

Cohort genes with a PharmGKB record: 11; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

28 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)
OSIMERTINIB	4	VHL
BRIGATINIB	4	VHL
CRIZOTINIB	4	VHL
SALMETEROL XINAFOATE	4	MTOR
IMIPRAMINE	4	MTOR
AMOXAPINE	4	MTOR
IDARUBICIN	4	MTOR
TETRABENAZINE	4	MTOR
MIFEPRISTONE	4	MTOR
ZIPRASIDONE HYDROCHLORIDE	4	MTOR
PIMOZIDE	4	MTOR
NAFTOPIDIL	4	MTOR
NICLOSAMIDE	4	MTOR
FELODIPINE	4	MTOR
NICARDIPINE	4	MTOR
AZACITIDINE	4	MTOR
TRIFLUPERIDOL	4	MTOR
CYCLOSPORINE	4	MTOR
CLEMASTINE	4	MTOR
TERFENADINE	4	MTOR
FLUOROURACIL	4	MTOR
PANCURONIUM	4	MTOR
EVEROLIMUS	4	MTOR
NIFEDIPINE	4	MTOR
PRAZOSIN	4	MTOR
MAPROTILINE	4	MTOR
DOMPERIDONE	4	MTOR
ALPELISIB	4	MTOR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	VHL, MTOR, ATM
B	Phased (≥1) drug, not yet approved	1	PBRM1
C	Druggable family + PDB, no drug	3	OGG1, MAGI1, BAP1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	RNF2, ARID1A, GNAS, HNF1A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ARID1A	6	PBRM1
RNF2	16	—
GNAS	0	—
HNF1A	1	—
OGG1	19	—
MAGI1	4	—
BAP1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 253.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	105
PHASE1	52
PHASE1/PHASE2	40
Not specified	30
PHASE3	16
EARLY_PHASE1	7
PHASE4	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01521715	PHASE4	COMPLETED	First Line Pazopanib in Poor Risk Patients With Metastatic Renal Cell Carcinoma
NCT02570789	PHASE4	TERMINATED	Evaluation of Predictive Markers for Toxicity and Efficacy in Patients With mccRCC Treated by Anti-VEGF Therapy
NCT01575548	PHASE3	ACTIVE_NOT_RECRUITING	Pazopanib Hydrochloride in Treating Patients With Metastatic Kidney Cancer Who Have No Evidence of Disease After Surgery
NCT03793166	PHASE3	ACTIVE_NOT_RECRUITING	Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, The PDIGREE Study
NCT04510597	PHASE3	RECRUITING	Comparing the Outcome of Immunotherapy-Based Drug Combination Therapy With or Without Surgery to Remove the Kidney in Metastatic Kidney Cancer, the PROBE Trial
NCT04810078	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Subcutaneous Nivolumab Versus Intravenous Nivolumab in Participants With Previously Treated Clear Cell Renal Cell Carcinoma That is Advanced or Has Spread
NCT06661720	PHASE3	RECRUITING	Testing the Addition of the Anti-Cancer Drug Tivozanib to Immunotherapy (Pembrolizumab) After Surgery to Remove All Known Sites of Kidney Cancer
NCT06750419	PHASE3	RECRUITING	89Zr-TLX250 for PET/CT Imaging of ccRCC - ZIRCON-CP Study
NCT07000149	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Investigate the Efficacy and Safety of Volrustomig ± Casdatifan vs Nivolumab + Ipilimumab as 1L Treatment for Advanced ccRCC
NCT07011719	PHASE3	RECRUITING	Study of Casdatifan and Cabozantinib Versus Placebo and Cabozantinib in Patients With Advanced Clear Cell Renal Cell Carcinoma
NCT07197580	PHASE3	RECRUITING	Phase 3 Study to Assess Safety and Efficacy of 177Lu-TLX250 in Advanced Relapsed or Recurrent ccRCC
NCT07383441	PHASE3	NOT_YET_RECRUITING	Adding Biotherapy or Placebo to Standard Treatment for Advanced Kidney Cancer
NCT00326898	PHASE3	COMPLETED	Sunitinib Malate or Sorafenib Tosylate in Treating Patients With Kidney Cancer That Was Removed By Surgery
NCT00397345	PHASE3	COMPLETED	TroVax Renal Immunotherapy Survival Trial
NCT01198158	PHASE3	TERMINATED	Everolimus With or Without Bevacizumab in Treating Patients With Advanced Kidney Cancer That Progressed After First-Line Therapy
NCT01599754	PHASE3	TERMINATED	Adjuvant Axitinib Therapy of Renal Cell Cancer in High Risk Patients
NCT02535351	PHASE3	TERMINATED	Targeted Therapy With or Without Nephrectomy in Metastatic Renal Cell Carcinoma: Liquid Biopsy for Biomarkers Discovery
NCT03849118	PHASE3	COMPLETED	89Zr-TLX250 for PET/CT Imaging of ccRCC- ZIRCON Study
NCT07084909	PHASE2/PHASE3	WITHDRAWN	Piflufolastat F 18 PET/CT in Patients With Suspected, or at High Risk for Metastatic ccRCC
NCT01038778	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Entinostat in Combination With Aldesleukin in Treating Patients With Metastatic Kidney Cancer
NCT01684397	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Pazopanib Hydrochloride and Bevacizumab in Treating Patients With Previously Untreated Metastatic Kidney Cancer
NCT03092856	PHASE2	ACTIVE_NOT_RECRUITING	Axitinib With or Without Anti-OX40 Antibody PF-04518600 in Treating Patients With Metastatic Kidney Cancer
NCT03284385	PHASE2	ACTIVE_NOT_RECRUITING	Testing AZD1775 in Advanced Solid Tumors That Have a Mutation Called SETD2
NCT03308396	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study of Durvalumab and Guadecitabine in Advanced Kidney Cancer
NCT03438708	PHASE2	ACTIVE_NOT_RECRUITING	Prior Axitinib as a Determinant of Outcome of Renal Surgery
NCT03634540	PHASE2	ACTIVE_NOT_RECRUITING	A Trial of Belzutifan (PT2977, MK-6482) in Combination With Cabozantinib in Patients With Clear Cell Renal Cell Carcinoma (ccRCC) (MK-6482-003)
NCT03682289	PHASE2	ACTIVE_NOT_RECRUITING	Ceralasertib (AZD6738) Alone and in Combination With Olaparib or Durvalumab in Patients With Solid Tumors
NCT03972657	PHASE1/PHASE2	RECRUITING	A Trial to Find Out if REGN5678 (Nezastomig) is Safe and How Well it Works Alone or in Combination With Cemiplimab for Adult Participants With Metastatic Castration-Resistant Prostate Cancer and Other Tumors
NCT04022343	PHASE2	ACTIVE_NOT_RECRUITING	Neoadjuvant Cabozantinib in Treating Patients With Locally Advanced Kidney Cancer
NCT04071223	PHASE2	ACTIVE_NOT_RECRUITING	Testing the Addition of a New Anti-cancer Drug, Radium-223 Dichloride, to the Usual Treatment (Cabozantinib) for Advanced Renal Cell Cancer That Has Spread to the Bone, RadiCaL Study
NCT04802876	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Tislelizumab and Spartalizumab Across Multiple Cancer-types in Patients with PD1-high MRNA Expressing Tumors
NCT04977453	PHASE1/PHASE2	RECRUITING	GI-101/GI-101A as a Single Agent or in Combination With Pembrolizumab or Lenvatinib in Advanced Solid Tumors
NCT05012371	PHASE2	ACTIVE_NOT_RECRUITING	Lenvatinib With Everolimus Versus Cabozantinib for Second-Line or Third-Line Treatment of Metastatic Renal Cell Cancer
NCT05086692	PHASE1/PHASE2	RECRUITING	A Beta-only IL-2 ImmunoTherapY Study
NCT05199272	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Phase 1/2a Study of 23ME-00610 in Patients With Advanced Solid Malignancies
NCT05239533	PHASE2	ACTIVE_NOT_RECRUITING	Study of Nivolumab in Combination With 177Lu-girentuximab for Kidney Cancer
NCT05263050	PHASE2	RECRUITING	Trial of an Alternative Cabozantinib Dosing Schedule in Metastatic Renal Cell Carcinoma and Neuroendocrine Tumors
NCT05286294	PHASE2	ACTIVE_NOT_RECRUITING	Microbiota Transplant to Cancer Patients Who Have Failed Immunotherapy Using Faeces From Clinical Responders
NCT05361720	PHASE2	RECRUITING	Genetic Testing to Select Therapy for the Treatment of Advanced or Metastatic Kidney Cancer, OPTIC RCC Study
NCT05363631	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Seleno-L Methionine (SLM)-Axitinib-Pembrolizumab

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SORAFENIB	4	11
AXITINIB	4	9
CABOZANTINIB	4	9
PAZOPANIB	4	9
BELZUTIFAN	4	6
TIVOZANIB	4	4
TORIPALIMAB	4	4
IPILIMUMAB	4	3
SUNITINIB MALATE	4	3
ALDESLEUKIN	4	2
FLUDEOXYGLUCOSE F 18	4	2
LUTETIUM LU-177 VIPIVOTIDE TETRAXETAN	4	2
MAVORIXAFOR	4	2
RADIUM RA 223 DICHLORIDE	4	2
TEMSIROLIMUS	4	2
ADAGRASIB	4	1
AVELUMAB	4	1
CEMIPLIMAB	4	1
DACTINOMYCIN	4	1
DOSTARLIMAB	4	1
ERLOTINIB	4	1
HYALURONIDASE (HUMAN RECOMBINANT)	4	1
INULIN	4	1
IOFLUPANE	4	1
IXABEPILONE	4	1
LENVATINIB	4	1
NIRAPARIB	4	1
NIVOLUMAB	4	1
PANOBINOSTAT	4	1
RELATLIMAB	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 8 predictive associations from 8 curated evidence items; also 50 oncogenic, 8 prognostic, 1 diagnostic.

Molecular subtype	Therapy	Effect	Level	CIViC
PBRM1 Mutation	CTLA-4 Inhibitor + Anti-PD-L1 Monoclonal Antibody	Sensitivity/Response	CIViC B	EID7247
BAP1 Q267fs	Niraparib	Sensitivity/Response	CIViC C	EID11199
BRD4 Overexpression	JQ1	Sensitivity/Response	CIViC D	EID2957
MTOR E1799K	Sirolimus	Sensitivity/Response	CIViC D	EID1321
MTOR Q2223K	Temsirolimus	Sensitivity/Response	CIViC D	EID4522
SETD2 Loss	ATR Inhibitor + Anti-PD1 Monoclonal Antibody	Sensitivity/Response	CIViC D	EID12580
SETD2 Loss	Akt Inhibitor MK2206 + TGX221 + PI3Kbeta Inhibitor AZD8186	Sensitivity/Response	CIViC D	EID12581
TERT Overexpression	UO126	Sensitivity/Response	CIViC D	EID2900