Prostate cancer, hereditary, 1

Summary

Prostate cancer, hereditary, 1 (MONDO:0011098) is a cancer with 9 cohort genes (8 CIViC-evidence somatic drivers; 1,307 ClinVar predisposition records). The dominant Reactome pathway is Signaling by RAS GAP mutants (3 cohort genes).

At a glance

• Classification: Cancer
• Cohort genes: 9
• ClinVar variants: 1,307

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	prostate cancer, hereditary, 1
Mondo ID	MONDO:0011098
OMIM	601518
UMLS	C4722327
MedGen	1648436
GARD	0015334
Is cancer (heuristic)	yes

Also known as: familial prostate cancer caused by mutation in RNASEL · HPC1 · prostate cancer 1 · prostate cancer, hereditary, 1 · prostate cancer, hereditary, type 1 · RNASEL familial prostate cancer

Data availability: 1,307 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › prostate cancer, hereditary › prostate cancer, hereditary, 1

Related subtypes (17): prostate cancer, hereditary, X-linked 1, prostate cancer, hereditary, X-linked 2, prostate cancer, hereditary, 8, prostate cancer, hereditary, 3, prostate cancer, hereditary, 4, prostate cancer, hereditary, 5, prostate cancer, hereditary, 6, prostate cancer, hereditary, 7, prostate cancer, hereditary, 9, prostate cancer, hereditary, 10, prostate cancer, hereditary, 12, prostate cancer, hereditary, 13, prostate cancer, hereditary, 11, prostate cancer, hereditary, 14, prostate cancer, hereditary, 15, prostate cancer, hereditary, 2, familial prostate carcinoma

Genetics & variants

GWAS landscape

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

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

546 uncertain significance, 20 pathogenic, 13 likely benign, 7 likely pathogenic, 4 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 4 benign/likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
202193	NM_004333.6(BRAF):c.1783T>C (p.Phe595Leu)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372572	NM_004333.6(BRAF):c.1390G>A (p.Gly464Arg)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
12596	NM_004985.5(KRAS):c.13A>G (p.Lys5Glu)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068748	NM_000314.8(PTEN):c.440del (p.Lys147fs)	PTEN	Pathogenic	criteria provided, single submitter
1424596	NM_000314.8(PTEN):c.463del (p.Tyr155fs)	PTEN	Pathogenic	criteria provided, single submitter
1451490	NM_000314.8(PTEN):c.428del (p.Gly143fs)	PTEN	Pathogenic	criteria provided, single submitter
1454161	NM_000314.8(PTEN):c.270del (p.Phe90fs)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
1734391	NM_000314.8(PTEN):c.372T>G (p.Cys124Trp)	PTEN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1741948	NM_000314.8(PTEN):c.461del (p.Phe154fs)	PTEN	Pathogenic	criteria provided, single submitter
2110542	NM_000314.8(PTEN):c.404dup (p.Cys136fs)	PTEN	Pathogenic	criteria provided, single submitter
2674311	NM_000314.8(PTEN):c.400del (p.Val133_Met134insTer)	PTEN	Pathogenic	criteria provided, single submitter
2687606	NM_000314.8(PTEN):c.457del (p.Asp153fs)	PTEN	Pathogenic	criteria provided, single submitter
2687626	NM_000314.8(PTEN):c.432dup (p.Phe145fs)	PTEN	Pathogenic	criteria provided, single submitter
492325	NM_000314.8(PTEN):c.306del (p.Lys102fs)	PTEN	Pathogenic	criteria provided, multiple submitters, no conflicts
646006	NM_000314.8(PTEN):c.476G>A (p.Arg159Lys)	PTEN	Pathogenic	reviewed by expert panel
13005	NM_021133.4(RNASEL):c.3G>A (p.Met1Ile)	RNASEL	Pathogenic	no assertion criteria provided
1026335	NM_000546.6(TP53):c.476C>A (p.Ala159Asp)	TP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1366432	NM_000546.6(TP53):c.388del (p.Leu130fs)	TP53	Pathogenic	criteria provided, multiple submitters, no conflicts
1453627	NM_000546.6(TP53):c.378C>A (p.Tyr126Ter)	TP53	Pathogenic	criteria provided, multiple submitters, no conflicts
2687634	NM_000546.6(TP53):c.531CCA[1] (p.His179del)	TP53	Pathogenic	criteria provided, single submitter
2687646	NM_000546.6(TP53):c.532dup (p.His178fs)	TP53	Pathogenic	criteria provided, multiple submitters, no conflicts
2687675	NM_000546.6(TP53):c.499_500del (p.Gln167fs)	TP53	Pathogenic	criteria provided, multiple submitters, no conflicts
2687678	NM_000546.6(TP53):c.516del (p.Val172_Val173insTer)	TP53	Pathogenic	criteria provided, single submitter
659670	NM_000546.6(TP53):c.383del (p.Pro128fs)	TP53	Pathogenic	criteria provided, multiple submitters, no conflicts
44813	NM_004333.6(BRAF):c.1780G>A (p.Asp594Asn)	BRAF	Likely pathogenic	criteria provided, single submitter
1406308	NM_000314.8(PTEN):c.334C>G (p.Leu112Val)	PTEN	Likely pathogenic	reviewed by expert panel
1709670	NM_000314.8(PTEN):c.471del (p.Glu157_Val158insTer)	PTEN	Likely pathogenic	criteria provided, single submitter
2502558	NM_000314.8(PTEN):c.361G>A (p.Ala121Thr)	PTEN	Likely pathogenic	criteria provided, single submitter
2562403	NM_000314.8(PTEN):c.322C>T (p.Leu108Phe)	PTEN	Likely pathogenic	criteria provided, single submitter
2687614	NM_000314.8(PTEN):c.361G>C (p.Ala121Pro)	PTEN	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 70 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
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
TP53	LoF	ACC,ALL,AML,ANGS,ANSC,BCC,BL,BLADDER,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,CHRCC,CLLSLL,COAD,COADREAD,CSCC,DLBCLNOS,EGC,ES,ESCA,ESCC,GB,GBC,GBM,GIST,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LMS,LNM,LUAD,LUSC,MBL,MEL,MLYM,MT,NBL,NETNOS,NHL,NPC,NSCLC,OS,OVT,PAAD,PANCREAS,PAST,PCM,PLMESO,PRAD,PRCC,PROSTATE,RCC,READ,SACA,SARCNOS,SCLC,SIC,SKCM,SKIN,SOFT_TISSUE,STAD,STOMACH,THYM,UCEC,UCS,UTUC,VULVA,WDTC,WT	CIViC #45
VEGFA			CIViC #6071
HOXB13			CIViC #8351
HRAS	Act	ANGS,BLCA,BRCA,COADREAD,CSCC,HNSC,LUSC,NPC,PGNG,PRAD,PROSTATE,THYM,UTUC,WDTC	CIViC #2747
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
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
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

GenCC gene–disease validity (cohort genes)

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

Gene	Classification	Inheritance	Disease	Records
RNASEL	Limited	Autosomal dominant	prostate cancer, hereditary, 1	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNASEL	Orphanet:1331	Familial prostate cancer
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
TP53	Orphanet:1333	Familial pancreatic carcinoma
TP53	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
TP53	Orphanet:1501	Adrenocortical carcinoma
TP53	Orphanet:210159	Adult hepatocellular carcinoma
TP53	Orphanet:251576	Gliosarcoma
TP53	Orphanet:251579	Giant cell glioblastoma
TP53	Orphanet:251899	Choroid plexus carcinoma
TP53	Orphanet:2807	Papilloma of choroid plexus
TP53	Orphanet:293199	Pleomorphic rhabdomyosarcoma
TP53	Orphanet:3318	Essential thrombocythemia
TP53	Orphanet:524	Li-Fraumeni syndrome
TP53	Orphanet:52688	Myelodysplastic syndrome
TP53	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
TP53	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
TP53	Orphanet:668	Osteosarcoma
TP53	Orphanet:67038	B-cell chronic lymphocytic leukemia
TP53	Orphanet:70573	Small cell lung cancer
TP53	Orphanet:96253	Cushing disease
TP53	Orphanet:99756	Alveolar rhabdomyosarcoma
TP53	Orphanet:99757	Embryonal rhabdomyosarcoma
HOXB13	Orphanet:1331	Familial prostate cancer
HRAS	Orphanet:146	Differentiated thyroid carcinoma
HRAS	Orphanet:2612	Linear nevus sebaceus syndrome
HRAS	Orphanet:2874	Phakomatosis pigmentokeratotica
HRAS	Orphanet:3071	Costello syndrome
HRAS	Orphanet:79414	Woolly hair nevus
KRAS	Orphanet:1333	Familial pancreatic carcinoma
KRAS	Orphanet:1340	Cardiofaciocutaneous syndrome
KRAS	Orphanet:144	Lynch syndrome
KRAS	Orphanet:146	Differentiated thyroid carcinoma
KRAS	Orphanet:2396	Encephalocraniocutaneous lipomatosis
KRAS	Orphanet:251615	Pilomyxoid astrocytoma
KRAS	Orphanet:2612	Linear nevus sebaceus syndrome
KRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease
KRAS	Orphanet:3339	Oculoectodermal syndrome
KRAS	Orphanet:648	Noonan syndrome
KRAS	Orphanet:86834	Juvenile myelomonocytic leukemia
NRAS	Orphanet:146	Differentiated thyroid carcinoma

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNASEL	HGNC:10050	ENSG00000135828	Q05823	2-5A-dependent ribonuclease	gencc,clinvar
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	clinvar
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	clinvar
VEGFA	HGNC:12680	ENSG00000112715	P15692	Vascular endothelial growth factor A, long form	clinvar
HOXB13	HGNC:5112	ENSG00000159184	Q92826	Homeobox protein Hox-B13	clinvar
HRAS	HGNC:5173	ENSG00000174775	P01112	GTPase HRas	clinvar
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	clinvar
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	clinvar
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNASEL	2-5A-dependent ribonuclease	Endoribonuclease that functions in the interferon (IFN) antiviral response.
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
VEGFA	Vascular endothelial growth factor A, long form	Participates in the induction of key genes involved in the response to hypoxia and in the induction of angiogenesis such as HIF1A.
HOXB13	Homeobox protein Hox-B13	Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.
HRAS	GTPase HRas	Involved in the activation of Ras protein signal transduction.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
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.

Protein-family classification

Druggable: 5 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.56

Family distribution

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

Family	Genes	Fold	FDR
Kinase	2	6.2×	0.198
Phosphatase	1	9.3×	0.256
Enzyme (other)	2	2.7×	0.282
Transcription factor	2	1.8×	0.374
Other/Unknown	2	0.4×	0.992

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNASEL	Kinase	yes	4.6.1.19	Prot_kinase_dom, Ankyrin_rpt, KEN_dom
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
VEGFA	Other/Unknown	no		PDGF/VEGF_dom, PD_growth_factor_CS, VEGF_C
HOXB13	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
HRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
NRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom

Expression context

Cohort genes with no expression data: 0.

9 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
amniotic fluid	1
germinal epithelium of ovary	1
palpebral conjunctiva	1
buccal mucosa cell	1
colonic epithelium	1
ganglionic eminence	1
tendon of biceps brachii	1
ventricular zone	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1
mucosa of sigmoid colon	1
prostate gland	1
rectum	1
skin of abdomen	1
skin of leg	1
zone of skin	1
nipple	1
pylorus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNASEL	249	ubiquitous	marker	amniotic fluid, palpebral conjunctiva, germinal epithelium of ovary
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
VEGFA	297	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
HOXB13	38	broad	marker	rectum, mucosa of sigmoid colon, prostate gland
HRAS	139	ubiquitous	marker	skin of abdomen, skin of leg, zone of skin
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte
PTEN	256	ubiquitous	marker	sperm, endothelial cell, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 13.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
KRAS	14,509
PTEN	11,626
HRAS	8,064
NRAS	7,598
BRAF	7,394
RNASEL	6,889
HOXB13	1,393
VEGFA	167

Intra-cohort edges

A	B	Sources
BRAF	HRAS	intact, string_interaction
BRAF	KRAS	biogrid_interaction, intact, string_interaction
BRAF	NRAS	biogrid_interaction, intact, string_interaction
BRAF	PTEN	biogrid_interaction, string_interaction
BRAF	TP53	string_interaction
HRAS	TP53	string_interaction
KRAS	NRAS	intact
KRAS	PTEN	string_interaction
KRAS	TP53	string_interaction
NRAS	PTEN	string_interaction
NRAS	TP53	string_interaction
PTEN	TP53	string_interaction
RNASEL	TP53	intact

Structural data

PDB: 9 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
TP53	P04637	313
HRAS	P01112	246
BRAF	P15056	131
VEGFA	P15692	56
NRAS	P01111	35
PTEN	P60484	12
HOXB13	Q92826	10
RNASEL	Q05823	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 171. Enrichment computed across 9 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by RAS GAP mutants	3	1427.5×	2e-08	HRAS, KRAS, NRAS
Signaling by RAS GTPase mutants	3	1427.5×	2e-08	HRAS, KRAS, NRAS
VEGFR2 mediated cell proliferation	4	285.5×	3e-08	VEGFA, HRAS, KRAS, NRAS
Activation of RAS in B cells	3	856.5×	1e-07	HRAS, KRAS, NRAS
RAF activation	4	167.9×	2e-07	BRAF, HRAS, KRAS, NRAS
Signaling by high-kinase activity BRAF mutants	4	158.6×	2e-07	BRAF, HRAS, KRAS, NRAS
RAS signaling downstream of NF1 loss-of-function variants	3	611.8×	2e-07	HRAS, KRAS, NRAS
Estrogen-stimulated signaling through PRKCZ	3	611.8×	2e-07	HRAS, KRAS, NRAS
SOS-mediated signalling	3	535.3×	2e-07	HRAS, KRAS, NRAS
MAP2K and MAPK activation	4	142.8×	2e-07	BRAF, HRAS, KRAS, NRAS
Signaling by RAF1 mutants	4	139.3×	2e-07	BRAF, HRAS, KRAS, NRAS
Negative regulation of MAPK pathway	4	132.8×	2e-07	BRAF, HRAS, KRAS, NRAS
Signaling by moderate kinase activity BRAF mutants	4	126.9×	2e-07	BRAF, HRAS, KRAS, NRAS
Paradoxical activation of RAF signaling by kinase inactive BRAF	4	126.9×	2e-07	BRAF, HRAS, KRAS, NRAS
Signaling downstream of RAS mutants	4	126.9×	2e-07	BRAF, HRAS, KRAS, NRAS
Activated NTRK3 signals through RAS	3	475.8×	2e-07	HRAS, KRAS, NRAS
EGFR Transactivation by Gastrin	3	428.2×	2e-07	HRAS, KRAS, NRAS
SHC-related events triggered by IGF1R	3	428.2×	2e-07	HRAS, KRAS, NRAS
Activated NTRK2 signals through RAS	3	428.2×	2e-07	HRAS, KRAS, NRAS
MET activates RAS signaling	3	389.3×	3e-07	HRAS, KRAS, NRAS
Signaling by FGFR4 in disease	3	356.9×	4e-07	HRAS, KRAS, NRAS
Activated NTRK2 signals through FRS2 and FRS3	3	356.9×	4e-07	HRAS, KRAS, NRAS
Constitutive Signaling by Overexpressed ERBB2	3	356.9×	4e-07	HRAS, KRAS, NRAS
p38MAPK events	3	329.4×	4e-07	HRAS, KRAS, NRAS
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	3	329.4×	4e-07	HRAS, KRAS, NRAS
Signaling by PDGFRA extracellular domain mutants	3	329.4×	4e-07	HRAS, KRAS, NRAS
Signaling by BRAF and RAF1 fusions	4	85.2×	5e-07	BRAF, HRAS, KRAS, NRAS
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	3	305.9×	5e-07	HRAS, KRAS, NRAS
GRB2 events in EGFR signaling	3	285.5×	6e-07	HRAS, KRAS, NRAS
Erythropoietin activates RAS	3	285.5×	6e-07	HRAS, KRAS, NRAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Ras protein signal transduction	4	91.3×	2e-05	TP53, HRAS, KRAS, NRAS
MAPK cascade	4	68.1×	4e-05	BRAF, HRAS, KRAS, NRAS
neuron apoptotic process	3	61.7×	0.002	TP53, HRAS, KRAS
positive regulation of cellular senescence	2	288.1×	0.002	TP53, KRAS
regulation of long-term neuronal synaptic plasticity	2	220.3×	0.003	HRAS, KRAS
glial cell proliferation	2	197.1×	0.003	TP53, KRAS
positive regulation of gene expression	4	17.2×	0.003	BRAF, TP53, VEGFA, KRAS
negative regulation of neuron apoptotic process	3	37.0×	0.003	BRAF, HRAS, KRAS
cellular response to gamma radiation	2	133.8×	0.004	TP53, HRAS
positive regulation of ERK1 and ERK2 cascade	3	28.4×	0.005	BRAF, VEGFA, HRAS
positive regulation of transcription by RNA polymerase II	5	8.3×	0.005	RNASEL, TP53, VEGFA, HRAS, PTEN
homeostasis of number of cells within a tissue	2	98.5×	0.005	VEGFA, KRAS
negative regulation of epithelial to mesenchymal transition	2	91.3×	0.005	VEGFA, PTEN
T cell differentiation in thymus	2	91.3×	0.005	BRAF, TP53
fibroblast proliferation	2	87.1×	0.006	TP53, HRAS
neuroblast proliferation	2	81.4×	0.006	TP53, VEGFA
intrinsic apoptotic signaling pathway	2	79.7×	0.006	TP53, HRAS
basophil chemotaxis	1	1872.4×	0.008	VEGFA
positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway	1	1872.4×	0.008	VEGFA
negative regulation of helicase activity	1	1872.4×	0.008	TP53
response to mineralocorticoid	1	1872.4×	0.008	KRAS
cellular response to actinomycin D	1	1872.4×	0.008	TP53
regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	1872.4×	0.008	TP53
negative regulation of G1 to G0 transition	1	1872.4×	0.008	TP53
visual learning	2	68.1×	0.008	BRAF, KRAS
cellular senescence	2	65.7×	0.008	TP53, HRAS
positive regulation of epithelial cell proliferation	2	54.3×	0.008	VEGFA, HRAS
cellular response to xenobiotic stimulus	2	53.5×	0.008	BRAF, TP53
positive regulation of endothelial cell proliferation	2	51.3×	0.008	VEGFA, NRAS
coronary vein morphogenesis	1	936.2×	0.009	VEGFA

Therapeutics

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 5 · Phased (≥1): 6 · Undrugged: 3

Druggability breadth: 8 of 9 evidence-associated genes (89%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

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

Symbol	Example approved molecule
BRAF	VEMURAFENIB
TP53	NITROFURANTOIN
VEGFA	VADADUSTAT
HRAS	LONAFARNIB
KRAS	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
BRAF	48	4
KRAS	11	4
VEGFA	5	4
HRAS	4	4
NRAS	1	1
RNASEL	0	0
HOXB13	0	0
PTEN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF, KRAS
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF, KRAS
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
KRAS	861	Binding:829, Functional:32
VEGFA	64	Binding:64
HRAS	48	Binding:45, Functional:3
RNASEL	43	Binding:42, Functional:1
NRAS	18	Binding:18
PTEN	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNASEL	4.6.1.19	ribonuclease T2
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
HRAS	3.6.5.2	small monomeric GTPase
KRAS	3.6.5.2	small monomeric GTPase
PTEN	3.1.3.16, 3.1.3.67	protein-serine/threonine phosphatase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BRAF	1,442
TP53	869
KRAS	861

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

30 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)
VEMURAFENIB	4	BRAF, KRAS
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF, KRAS
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	BRAF, TP53, VEGFA, HRAS, KRAS
B	Phased (≥1) drug, not yet approved	1	NRAS
C	Druggable family + PDB, no drug	2	RNASEL, PTEN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	HOXB13

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PTEN	8	TP53
RNASEL	43	—
HOXB13	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.