Capillary malformation-arteriovenous malformation 1

Summary

Capillary malformation-arteriovenous malformation 1 (MONDO:0020783) is a disease caused by RASA1 (GenCC Definitive), with 4 cohort genes. The dominant Reactome pathway is Downstream signal transduction (3 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: RASA1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 151
• Phenotypes (HPO): 44

Clinical features

Signs & symptoms

Clinical features (HPO)

44 HPO clinical features (Orphanet curated; top 44 by frequency):

HPO ID	Term	Frequency
HP:0002814	Abnormality of the lower limb	Very frequent (80-99%)
HP:0100026	Arteriovenous malformation	Very frequent (80-99%)
HP:0001722	High-output congestive heart failure	Frequent (30-79%)
HP:0002617	Dilatation	Frequent (30-79%)
HP:0002619	Varicose veins	Frequent (30-79%)
HP:0004947	Arteriovenous fistula	Frequent (30-79%)
HP:0004948	Vascular tortuosity	Frequent (30-79%)
HP:0007394	Prominent superficial blood vessels	Frequent (30-79%)
HP:0008968	Muscle hypertrophy of the lower extremities	Frequent (30-79%)
HP:0012721	Venous malformation	Frequent (30-79%)
HP:0025104	Capillary malformation	Frequent (30-79%)
HP:0025474	Erythematous plaque	Frequent (30-79%)
HP:0032555	Bounding pulse	Frequent (30-79%)
HP:0100553	Hemihypertrophy of lower limb	Frequent (30-79%)
HP:0100784	Peripheral arteriovenous fistula	Frequent (30-79%)
HP:0000016	Urinary retention	Occasional (5-29%)
HP:0000079	Abnormality of the urinary system	Occasional (5-29%)
HP:0000100	Nephrotic syndrome	Occasional (5-29%)
HP:0001892	Abnormal bleeding	Occasional (5-29%)
HP:0002138	Subarachnoid hemorrhage	Occasional (5-29%)
HP:0002196	Myelopathy	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002390	Spinal arteriovenous malformation	Occasional (5-29%)
HP:0002408	Cerebral arteriovenous malformation	Occasional (5-29%)
HP:0002817	Abnormality of the upper limb	Occasional (5-29%)
HP:0002936	Distal sensory impairment	Occasional (5-29%)
HP:0003418	Back pain	Occasional (5-29%)
HP:0003474	Somatic sensory dysfunction	Occasional (5-29%)
HP:0005521	Disseminated intravascular coagulation	Occasional (5-29%)
HP:0006489	Abnormality of the femoral metaphysis	Occasional (5-29%)
HP:0007340	Lower limb muscle weakness	Occasional (5-29%)
HP:0010484	Hypertrophy of the upper limb	Occasional (5-29%)
HP:0012514	Lower limb pain	Occasional (5-29%)
HP:0012531	Pain	Occasional (5-29%)
HP:0030833	Neck pain	Occasional (5-29%)
HP:0031138	Abnormal B-type natriuretic peptide level	Occasional (5-29%)
HP:0031939	Conus terminalis arteriovenous malformation	Occasional (5-29%)
HP:0040189	Scaling skin	Occasional (5-29%)
HP:0100749	Chest pain	Occasional (5-29%)
HP:0100766	Abnormal lymphatic vessel morphology	Occasional (5-29%)
HP:0100775	Dural ectasia	Occasional (5-29%)
HP:0200042	Skin ulcer	Occasional (5-29%)
HP:0007461	Hemangiomatosis	Very rare (<1-4%)
HP:0010550	Paraplegia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	capillary malformation-arteriovenous malformation 1
Mondo ID	MONDO:0020783
OMIM	608354, 608355
Orphanet	90307, 693907
SNOMED CT	234143003
UMLS	C4747394
MedGen	1648501
GARD	0009787
Is cancer (heuristic)	no

Also known as: capillary malformation-arteriovenous malformation 1 · CMAVM1 · RASA1-related capillary malformation-arteriovenous malformation

Data availability: 151 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › capillary malformation-arteriovenous malformation syndrome › capillary malformation-arteriovenous malformation 1

Related subtypes (1): capillary malformation-arteriovenous malformation 2

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

151 retrieved; paginated sample, class counts are floors:

43 uncertain significance, 42 pathogenic, 26 likely pathogenic, 16 conflicting classifications of pathogenicity, 12 benign/likely benign, 7 pathogenic/likely pathogenic, 3 likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033551	NM_002890.3(RASA1):c.2532_2533delinsATTTGA (p.Asn844fs)	CCNH	Pathogenic	criteria provided, single submitter
1302016	NM_002890.3(RASA1):c.1460del (p.Gly487fs)	CCNH	Pathogenic	criteria provided, single submitter
1326256	NM_002890.3(RASA1):c.1201del (p.Ile401fs)	CCNH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1395909	NM_002890.3(RASA1):c.2891_2894del (p.Lys964fs)	CCNH	Pathogenic	criteria provided, multiple submitters, no conflicts
16000	NM_002890.3(RASA1):c.1619G>A (p.Cys540Tyr)	CCNH	Pathogenic	no assertion criteria provided
16001	NM_002890.3(RASA1):c.853C>T (p.Arg285Ter)	CCNH	Pathogenic	criteria provided, multiple submitters, no conflicts
16002	NM_002890.3(RASA1):c.829-9G>A	CCNH	Pathogenic	no assertion criteria provided
16003	NM_002890.3(RASA1):c.2252_2255dup (p.Ala753fs)	CCNH	Pathogenic	no assertion criteria provided
1684041	NM_002890.3(RASA1):c.1995_1999del (p.Ser665fs)	CCNH	Pathogenic	no assertion criteria provided
1691332	NM_002890.3(RASA1):c.2422_2423del (p.Gln808fs)	CCNH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1699012	NM_002890.3(RASA1):c.2655G>A (p.Trp885Ter)	CCNH	Pathogenic	criteria provided, single submitter
1706602	NM_002890.3(RASA1):c.2239C>T (p.Gln747Ter)	CCNH	Pathogenic	criteria provided, single submitter
1804998	NM_002890.3(RASA1):c.2474dup (p.Gln826fs)	CCNH	Pathogenic	criteria provided, single submitter
213660	NM_002890.3(RASA1):c.2131C>T (p.Arg711Ter)	CCNH	Pathogenic	criteria provided, multiple submitters, no conflicts
239412	NM_002890.3(RASA1):c.2529dup (p.Asn844Ter)	CCNH	Pathogenic	criteria provided, single submitter
2921092	NM_002890.3(RASA1):c.2691-1G>T	CCNH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3340430	NM_002890.3(RASA1):c.1050-1G>A	CCNH	Pathogenic	criteria provided, single submitter
3340433	NM_002890.3(RASA1):c.1453_1453+5del	CCNH	Pathogenic	criteria provided, single submitter
3340434	NM_002890.3(RASA1):c.2345-1G>C	CCNH	Pathogenic	criteria provided, single submitter
3340435	NM_002890.3(RASA1):c.1490dup (p.Leu497fs)	CCNH	Pathogenic	criteria provided, single submitter
3340436	NM_002890.3(RASA1):c.1333-1G>T	CCNH	Pathogenic	criteria provided, single submitter
3340442	NM_002890.3(RASA1):c.2041_2042dup (p.Gln681fs)	CCNH	Pathogenic	criteria provided, single submitter
3340453	NM_002890.3(RASA1):c.1934_1934+1del	CCNH	Pathogenic	criteria provided, single submitter
3600447	NM_002890.3(RASA1):c.2616T>G (p.Tyr872Ter)	CCNH	Pathogenic	criteria provided, multiple submitters, no conflicts
3774502	NM_002890.3(RASA1):c.1717C>T (p.Gln573Ter)	CCNH	Pathogenic	criteria provided, single submitter
411712	NM_002890.3(RASA1):c.1358_1359del (p.Thr453fs)	CCNH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
411713	NM_002890.3(RASA1):c.3055C>T (p.Gln1019Ter)	CCNH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
411714	NM_002890.3(RASA1):c.613_617del (p.Leu205fs)	CCNH	Pathogenic	criteria provided, multiple submitters, no conflicts
440234	NM_002890.3(RASA1):c.2035C>T (p.Arg679Ter)	CCNH	Pathogenic	criteria provided, multiple submitters, no conflicts
449560	NM_002890.3(RASA1):c.2125C>T (p.Arg709Ter)	CCNH	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 28 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

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

Gene	Classification	Inheritance	Disease	Records
RASA1	Definitive	Autosomal dominant	capillary malformation-arteriovenous malformation 1	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RASA1	Orphanet:693907	RASA1-related capillary malformation-arteriovenous malformation
RASA1	Orphanet:90307	Parkes Weber syndrome
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
PIK3CA	Orphanet:140944	CLOVES syndrome
PIK3CA	Orphanet:144	Lynch syndrome
PIK3CA	Orphanet:168984	CLAPO syndrome
PIK3CA	Orphanet:201	Cowden syndrome
PIK3CA	Orphanet:210159	Adult hepatocellular carcinoma
PIK3CA	Orphanet:221061	Familial cerebral cavernous malformation
PIK3CA	Orphanet:2495	Meningioma
PIK3CA	Orphanet:276280	Hemihyperplasia-multiple lipomatosis syndrome
PIK3CA	Orphanet:295239	Macrodactyly of fingers, unilateral
PIK3CA	Orphanet:295243	Macrodactyly of toes, unilateral
PIK3CA	Orphanet:314662	Segmental progressive overgrowth syndrome with fibroadipose hyperplasia
PIK3CA	Orphanet:60040	Megalencephaly-capillary malformation-polymicrogyria syndrome
PIK3CA	Orphanet:714737	Diffuse capillary malformation with overgrowth
PIK3CA	Orphanet:90308	Capillary-lymphatic-venous malformation with segmental distribution
PIK3CA	Orphanet:99802	Hemimegalencephaly

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RASA1	HGNC:9871	ENSG00000145715	P20936	Ras GTPase-activating protein 1	gencc,clinvar
CCNH	HGNC:1594	ENSG00000134480	P51946	Cyclin-H	clinvar
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	clinvar
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RASA1	Ras GTPase-activating protein 1	GTPase-activating protein (GAP) that stimulates the intrinsic GTPase activity of Ras proteins, such as NRAS, facilitating their transition from the active GTP-bound state to the inactive GDP-bound state, thereby terminating Ras signaling.
CCNH	Cyclin-H	Regulates CDK7, the catalytic subunit of the CDK-activating kinase (CAK) enzymatic complex.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
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.

Protein-family classification

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

Family distribution

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

Family	Genes	Fold	FDR
Kinase	1	6.9×	0.392
Scaffold/PPI	1	4.3×	0.392
Enzyme (other)	1	3.0×	0.392
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RASA1	Scaffold/PPI	no		C2_dom, SH2, SH3_domain
CCNH	Other/Unknown	no		Cyclin_N, Cyclin-like_dom, CyclinH/Ccl1
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
choroid plexus epithelium	1
endothelial cell	1
placenta	1
left testis	1
right testis	1
nipple	1
pylorus	1
trigeminal ganglion	1
adrenal tissue	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RASA1	298	ubiquitous	marker	endothelial cell, placenta, choroid plexus epithelium
CCNH	297	ubiquitous	marker	calcaneal tendon, left testis, right testis
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
PIK3CA	5,157
RASA1	4,407
CCNH	2,116

Intra-cohort edges

A	B	Sources
KRAS	PIK3CA	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
PIK3CA	P42336	135
CCNH	P51946	47
RASA1	P20936	15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 173. Enrichment computed across 4 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Downstream signal transduction	3	285.5×	1e-05	RASA1, KRAS, PIK3CA
Signaling by FGFR4 in disease	2	475.8×	3e-04	KRAS, PIK3CA
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	2	439.2×	3e-04	KRAS, PIK3CA
Signaling by PDGFRA extracellular domain mutants	2	439.2×	3e-04	KRAS, PIK3CA
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	2	407.9×	3e-04	RASA1, KRAS
Signaling by FLT3 ITD and TKD mutants	2	380.7×	3e-04	KRAS, PIK3CA
Constitutive Signaling by EGFRvIII	2	356.9×	3e-04	KRAS, PIK3CA
Signaling by ERBB2 ECD mutants	2	335.9×	3e-04	KRAS, PIK3CA
Tie2 Signaling	2	300.5×	3e-04	KRAS, PIK3CA
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	2	285.5×	3e-04	KRAS, PIK3CA
VEGFR2 mediated cell proliferation	2	285.5×	3e-04	RASA1, KRAS
Signaling by FLT3 fusion proteins	2	285.5×	3e-04	KRAS, PIK3CA
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	2	259.6×	3e-04	KRAS, PIK3CA
Signaling by FGFR3 in disease	2	248.3×	3e-04	KRAS, PIK3CA
Signaling by ERBB2 KD Mutants	2	211.5×	4e-04	KRAS, PIK3CA
DAP12 signaling	2	184.2×	5e-04	KRAS, PIK3CA
FLT3 Signaling	2	173.0×	5e-04	KRAS, PIK3CA
Signaling by CSF1 (M-CSF) in myeloid cells	2	173.0×	5e-04	KRAS, PIK3CA
Signaling by FGFR1 in disease	2	146.4×	6e-04	KRAS, PIK3CA
Signaling by FGFR2 in disease	2	132.8×	7e-04	KRAS, PIK3CA
Signaling by SCF-KIT	2	124.1×	8e-04	KRAS, PIK3CA
Regulation of RAS by GAPs	2	96.8×	0.001	RASA1, KRAS
Signaling by RAS GAP mutants	1	951.7×	0.008	KRAS
Signaling by RAS GTPase mutants	1	951.7×	0.008	KRAS
RAF/MAP kinase cascade	2	30.5×	0.011	KRAS, PIK3CA
Activation of RAS in B cells	1	571.0×	0.012	KRAS
MET activates PI3K/AKT signaling	1	475.8×	0.013	PIK3CA
Activated NTRK3 signals through PI3K	1	475.8×	0.013	PIK3CA
RAS signaling downstream of NF1 loss-of-function variants	1	407.9×	0.013	KRAS
Activated NTRK2 signals through PI3K	1	407.9×	0.013	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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of neuron apoptotic process	3	83.2×	3e-04	RASA1, KRAS, PIK3CA
response to muscle inactivity	1	4213.0×	0.004	PIK3CA
response to mineralocorticoid	1	4213.0×	0.004	KRAS
response to butyrate	1	4213.0×	0.004	PIK3CA
liver development	2	110.9×	0.004	KRAS, PIK3CA
forebrain astrocyte development	1	1404.3×	0.008	KRAS
response to L-leucine	1	1404.3×	0.008	PIK3CA
cellular response to hydrostatic pressure	1	1404.3×	0.008	PIK3CA
response to isolation stress	1	1053.2×	0.009	KRAS
response to gravity	1	702.2×	0.009	KRAS
negative regulation of actin filament depolymerization	1	702.2×	0.009	PIK3CA
regulation of cellular respiration	1	702.2×	0.009	PIK3CA
regulation of RNA metabolic process	1	702.2×	0.009	RASA1
regulation of actin filament organization	1	601.9×	0.009	PIK3CA
autosome genomic imprinting	1	601.9×	0.009	PIK3CA
negative regulation of fibroblast apoptotic process	1	601.9×	0.009	PIK3CA
actin cytoskeleton organization	2	39.6×	0.009	KRAS, PIK3CA
angiogenesis	2	31.2×	0.009	RASA1, PIK3CA
cardiac muscle cell contraction	1	421.3×	0.011	PIK3CA
positive regulation of protein localization to membrane	1	421.3×	0.011	PIK3CA
TORC2 signaling	1	383.0×	0.011	PIK3CA
type I pneumocyte differentiation	1	383.0×	0.011	KRAS
myoblast proliferation	1	351.1×	0.011	KRAS
phosphatidylinositol-3-phosphate biosynthetic process	1	324.1×	0.011	PIK3CA
anoikis	1	324.1×	0.011	PIK3CA
relaxation of cardiac muscle	1	324.1×	0.011	PIK3CA
positive regulation of cellular senescence	1	324.1×	0.011	KRAS
negative regulation of epithelial cell differentiation	1	300.9×	0.011	KRAS
response to dexamethasone	1	300.9×	0.011	PIK3CA
vasculature development	1	280.9×	0.011	PIK3CA

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
CCNH	ABEMACICLIB
KRAS	VEMURAFENIB
PIK3CA	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3CA	67	4
CCNH	28	4
KRAS	11	4
RASA1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ABEMACICLIB	4	CCNH
QUIZARTINIB	4	CCNH
ADAGRASIB	4	CCNH, KRAS
VEMURAFENIB	4	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
IDELALISIB	4	PIK3CA
ALPELISIB	4	PIK3CA
DUVELISIB	4	PIK3CA
COPANLISIB	4	PIK3CA
FEDRATINIB	4	PIK3CA
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	PIK3CA
ALVOCIDIB	3	CCNH
DINACICLIB	3	CCNH
LEROCICLIB	3	CCNH
OPNURASIB	3	KRAS
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	PIK3CA
TASELISIB	3	PIK3CA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PIK3CA	2,034	Binding:2009, ADMET:19, Toxicity:4, Functional:2
KRAS	861	Binding:829, Functional:32
CCNH	348	Binding:346, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KRAS	3.6.5.2	small monomeric GTPase
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

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CCNH	348
KRAS	861
PIK3CA	2,034

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ABEMACICLIB	4	CCNH
QUIZARTINIB	4	CCNH
ADAGRASIB	4	CCNH, KRAS
VEMURAFENIB	4	KRAS
DABRAFENIB	4	KRAS
LONAFARNIB	4	KRAS
SOTORASIB	4	KRAS
IDELALISIB	4	PIK3CA
ALPELISIB	4	PIK3CA
DUVELISIB	4	PIK3CA
COPANLISIB	4	PIK3CA
FEDRATINIB	4	PIK3CA
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	PIK3CA
ALVOCIDIB	3	CCNH
DINACICLIB	3	CCNH
LEROCICLIB	3	CCNH
OPNURASIB	3	KRAS
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	PIK3CA
TASELISIB	3	PIK3CA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	CCNH, KRAS, PIK3CA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RASA1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RASA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.