Vascular malformation

disease

On this page

Also known as malformation, vascularmalformations, vascular

Summary

Vascular malformation (MONDO:0024291) is a disease (an umbrella term covering 6 Mondo subtypes) caused by PIK3CA (GenCC Strong), with 12 cohort genes and 38 clinical trials. The dominant Reactome pathway is Tie2 Signaling (6 cohort genes). Top therapeutic interventions include bleomycin, enalapril, and alpelisib.

At a glance

Causal gene: PIK3CA (GenCC Strong)
Umbrella term: 6 Mondo subtypes
Cohort genes: 12
ClinVar variants: 52
Clinical trials: 38

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	vascular malformation
Mondo ID	MONDO:0024291
EFO	EFO:0006888
MeSH	D054079
UMLS	C0158570
MedGen	56387
Is cancer (heuristic)	no

Also known as: malformation, vascular · malformations, vascular · vascular malformation

Data availability: 52 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › vascular disorder › vascular malformation

Subtypes (6): glomuvenous malformation, congenital vascular malformation, EPHB4-associated vascular malformation spectrum, splenic venous malformation, cerebral proliferative angiopathy, fibro-adipose vascular anomaly

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

52 retrieved; paginated sample, class counts are floors:

20 pathogenic, 19 likely pathogenic, 8 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2691256	NM_004333.6(BRAF):c.1455_1469del (p.Leu485_Pro490delinsPhe)	BRAF	Pathogenic	no assertion criteria provided
44801	NM_004333.6(BRAF):c.1396G>A (p.Gly466Arg)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16001	NM_002890.3(RASA1):c.853C>T (p.Arg285Ter)	CCNH	Pathogenic	criteria provided, multiple submitters, no conflicts
2084347	NM_002890.3(RASA1):c.1916C>G (p.Ser639Ter)	CCNH	Pathogenic	criteria provided, multiple submitters, no conflicts
3774524	NM_002890.3(RASA1):c.1338_1341dup (p.Gln448fs)	CCNH	Pathogenic	criteria provided, single submitter
620150	NM_002890.3(RASA1):c.2365C>T (p.Arg789Ter)	CCNH	Pathogenic	criteria provided, multiple submitters, no conflicts
3774519	NM_002067.5(GNA11):c.546_547delinsTT (p.Arg183Cys)	GNA11	Pathogenic	criteria provided, single submitter
3340437	NM_005343.4(HRAS):c.197_217dup (p.Met72_Arg73insProMetArgAspGlnTyrMet)	HRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2691259	NM_002168.4(IDH2):c.516G>T (p.Arg172Ser)	IDH2	Pathogenic	no assertion criteria provided
12584	NM_004985.5(KRAS):c.34G>A (p.Gly12Ser)	KRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
376325	NM_033360.4(KRAS):c.64C>A (p.Gln22Lys)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4279990	NM_004985.5(KRAS):c.182_183delinsGT (p.Gln61Arg)	KRAS	Pathogenic	criteria provided, single submitter
45117	NM_004985.5(KRAS):c.183A>T (p.Gln61His)	KRAS	Pathogenic	criteria provided, single submitter
1691383	NM_002755.4(MAP2K1):c.173_187del (p.Gln58_Glu62del)	MAP2K1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
223140	NM_002755.4(MAP2K1):c.171G>T (p.Lys57Asn)	MAP2K1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2672096	NM_002755.4(MAP2K1):c.306_311del (p.Ile103_Lys104del)	MAP2K1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13900	NM_002524.5(NRAS):c.182A>G (p.Gln61Arg)	NRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
376261	NM_181523.3(PIK3R1):c.1690A>G (p.Asn564Asp)	PIK3R1	Pathogenic	criteria provided, single submitter
3774503	NM_181523.3(PIK3R1):c.1735delinsTTGATGTAAGTATTTGA (p.Gln579delinsLeuMetTer)	PIK3R1	Pathogenic	criteria provided, single submitter
3774527	NM_181523.3(PIK3R1):c.1746-2A>T	PIK3R1	Pathogenic	criteria provided, single submitter
1285389	NM_000459.5(TEK):c.3325G>T (p.Glu1109Ter)	TEK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1691346	NM_000459.5(TEK):c.2689T>C (p.Tyr897His)	TEK	Pathogenic	criteria provided, multiple submitters, no conflicts
1701565	NM_000459.5(TEK):c.3314_3316delinsACC (p.Thr1105_Thr1106delinsAsnPro)	TEK	Pathogenic	criteria provided, multiple submitters, no conflicts
2664276	NM_000459.5(TEK):c.3323_3324del (p.Leu1107_Tyr1108insTer)	TEK	Pathogenic	criteria provided, single submitter
3774515	NM_000459.5(TEK):c.3339del (p.Thr1112_Tyr1113insTer)	TEK	Pathogenic	criteria provided, single submitter
3774520	NM_000459.5(TEK):c.3339_3342del (p.Thr1112_Tyr1113insTer)	TEK	Pathogenic	criteria provided, single submitter
981227	NM_000459.5(TEK):c.2743C>T (p.Arg915Cys)	TEK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
981229	NM_000459.5(TEK):c.2740C>T (p.Leu914Phe)	TEK	Pathogenic	criteria provided, multiple submitters, no conflicts
1691375	NM_005343.4(HRAS):c.191_217dup (p.Met72_Arg73insHisSerAlaMetArgAspGlnTyrMet)	HRAS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3238637	NM_005343.4(HRAS):c.215_216insCTCCAGCGCCATGCGGGACCAGTACAT (p.Tyr71_Met72insIleSerSerAlaMetArgAspGlnTyr)	HRAS	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 78 · 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
PIK3CA	Strong	Autosomal dominant	megalencephaly-capillary malformation-polymicrogyria syndrome	9
MCF2L	Limited	Autosomal dominant	vascular malformation

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
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
TEK	Orphanet:1059	Blue rubber bleb nevus
TEK	Orphanet:2451	Mucocutaneous venous malformations
TEK	Orphanet:714806	Multifocal sporadic venous malformation
TEK	Orphanet:98976	Congenital glaucoma
GNA11	Orphanet:101049	Familial hypocalciuric hypercalcemia type 2
GNA11	Orphanet:1556	Cutis marmorata telangiectatica congenita
GNA11	Orphanet:39044	Uveal melanoma
GNA11	Orphanet:428	Autosomal dominant hypocalcemia
GNA11	Orphanet:675359	Anastomosing haemangioma
GNA11	Orphanet:714737	Diffuse capillary malformation with overgrowth
GNA11	Orphanet:79483	Phakomatosis cesioflammea
GNA11	Orphanet:79484	Phakomatosis cesiomarmorata
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
IDH2	Orphanet:163634	Maffucci syndrome
IDH2	Orphanet:251589	Anaplastic astrocytoma
IDH2	Orphanet:251598	Protoplasmic astrocytoma
IDH2	Orphanet:251601	Fibrillary astrocytoma
IDH2	Orphanet:251604	Gemistocytic astrocytoma
IDH2	Orphanet:251627	Oligodendroglioma
IDH2	Orphanet:251630	Anaplastic oligodendroglioma

Cohort genes → proteins

12 cohort genes, 12 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	12

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MCF2L	HGNC:14576	ENSG00000126217	O15068	Guanine nucleotide exchange factor DBS	gencc
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	gencc
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	clinvar
TEK	HGNC:11724	ENSG00000120156	Q02763	Angiopoietin-1 receptor	clinvar
CCNH	HGNC:1594	ENSG00000134480	P51946	Cyclin-H	clinvar
GNA11	HGNC:4379	ENSG00000088256	P29992	Guanine nucleotide-binding protein subunit alpha-11	clinvar
HRAS	HGNC:5173	ENSG00000174775	P01112	GTPase HRas	clinvar
IDH2	HGNC:5383	ENSG00000182054	P48735	Isocitrate dehydrogenase [NADP], mitochondrial	clinvar
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	clinvar
MAP2K1	HGNC:6840	ENSG00000169032	Q02750	Dual specificity mitogen-activated protein kinase kinase 1	clinvar
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	clinvar
PIK3R1	HGNC:8979	ENSG00000145675	P27986	Phosphatidylinositol 3-kinase regulatory subunit alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MCF2L	Guanine nucleotide exchange factor DBS	Guanine nucleotide exchange factor that catalyzes guanine nucleotide exchange on RHOA and CDC42, and thereby contributes to the regulation of RHOA and CDC42 signaling pathways.
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.
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
TEK	Angiopoietin-1 receptor	Tyrosine-protein kinase that acts as a cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskelet…
CCNH	Cyclin-H	Regulates CDK7, the catalytic subunit of the CDK-activating kinase (CAK) enzymatic complex.
GNA11	Guanine nucleotide-binding protein subunit alpha-11	Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.
HRAS	GTPase HRas	Involved in the activation of Ras protein signal transduction.
IDH2	Isocitrate dehydrogenase [NADP], mitochondrial	Plays a role in intermediary metabolism and energy production.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
MAP2K1	Dual specificity mitogen-activated protein kinase kinase 1	Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway.
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
PIK3R1	Phosphatidylinositol 3-kinase regulatory subunit alpha	Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane.

Protein-family classification

Druggable: 8 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.67

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	5	11.6×	2e-04
Enzyme (other)	3	3.0×	0.144
Scaffold/PPI	1	1.4×	0.681
Other/Unknown	3	0.5×	0.993

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MCF2L	Scaffold/PPI	no		DH_dom, CRAL-TRIO_dom, GDS_CDC24_CS
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
TEK	Kinase	yes	2.7.10.1	Prot_kinase_dom, EGF, Ser-Thr/Tyr_kinase_cat_dom
CCNH	Other/Unknown	no		Cyclin_N, Cyclin-like_dom, CyclinH/Ccl1
GNA11	Other/Unknown	no		Gprotein_alpha_Q, Gprotein_alpha_su, GproteinA_insert
HRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
IDH2	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom
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
NRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
PIK3R1	Kinase	yes	2.7.1.153	RhoGAP_dom, SH2, SH3_domain

Expression context

Cohort genes with no expression data: 0.

12 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)	12
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	4
secondary oocyte	2
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
adrenal tissue	1
tendon	1
buccal mucosa cell	1
colonic epithelium	1
diaphragm	1
right lung	1
visceral pleura	1
left testis	1
right testis	1
ileal mucosa	1
jejunal mucosa	1
pancreatic ductal cell	1
skin of abdomen	1
skin of leg	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MCF2L	253	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
TEK	223	broad	marker	right lung, diaphragm, visceral pleura
CCNH	297	ubiquitous	marker	calcaneal tendon, left testis, right testis
GNA11	299	ubiquitous	marker	ileal mucosa, jejunal mucosa, pancreatic ductal cell
HRAS	139	ubiquitous	marker	skin of abdomen, skin of leg, zone of skin
IDH2	292	ubiquitous	marker	apex of heart, gastrocnemius, hindlimb stylopod muscle
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
MAP2K1	298	ubiquitous	marker	secondary oocyte, oocyte, orbitofrontal cortex
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte
PIK3R1	294	ubiquitous	marker	calcaneal tendon, caput epididymis, corpus epididymis

Protein interactions among cohort

Intra-cohort edges: 16.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
HRAS	8,064
NRAS	7,598
BRAF	7,394
MAP2K1	5,944
PIK3R1	5,168
PIK3CA	5,157
IDH2	4,912
TEK	2,762
CCNH	2,116

Intra-cohort edges

A	B	Sources
BRAF	GNA11	intact, string_interaction
BRAF	HRAS	intact, string_interaction
BRAF	KRAS	biogrid_interaction, intact, string_interaction
BRAF	MAP2K1	biogrid_interaction, intact, string_interaction
BRAF	NRAS	biogrid_interaction, intact, string_interaction
BRAF	PIK3CA	biogrid_interaction, string_interaction
GNA11	NRAS	string_interaction
HRAS	MAP2K1	string_interaction
KRAS	MAP2K1	biogrid_interaction, string_interaction
KRAS	NRAS	intact
KRAS	PIK3CA	string_interaction
MAP2K1	NRAS	string_interaction
MAP2K1	PIK3CA	string_interaction
NRAS	PIK3CA	string_interaction
NRAS	PIK3R1	intact
PIK3CA	PIK3R1	biogrid_interaction, intact, string_interaction

Structural data

PDB: 11 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
HRAS	P01112	246
PIK3CA	P42336	135
BRAF	P15056	131
PIK3R1	P27986	105
MAP2K1	Q02750	94
CCNH	P51946	47
NRAS	P01111	35
TEK	Q02763	17
GNA11	P29992	13
IDH2	P48735	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MCF2L	O15068	77.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 282. Enrichment computed across 12 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Tie2 Signaling	6	300.5×	2e-12	TEK, HRAS, KRAS, NRAS, PIK3CA, PIK3R1
Signaling by FGFR4 in disease	5	396.5×	4e-11	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	5	366.0×	4e-11	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
Signaling by PDGFRA extracellular domain mutants	5	366.0×	4e-11	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
Signaling by FLT3 ITD and TKD mutants	5	317.2×	8e-11	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
Constitutive Signaling by EGFRvIII	5	297.4×	9e-11	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
RAF/MAP kinase cascade	8	40.7×	9e-11	BRAF, TEK, HRAS, KRAS, MAP2K1, NRAS, PIK3CA, PIK3R1
Signaling by ERBB2 ECD mutants	5	279.9×	1e-10	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	237.9×	2e-10	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
Signaling by FLT3 fusion proteins	5	237.9×	2e-10	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	216.3×	3e-10	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
Signaling by FGFR3 in disease	5	206.9×	4e-10	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
Signaling by ERBB2 KD Mutants	5	176.2×	8e-10	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
Downstream signal transduction	5	158.6×	1e-09	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
DAP12 signaling	5	153.5×	2e-09	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
FLT3 Signaling	5	144.2×	2e-09	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
RAF activation	5	139.9×	2e-09	BRAF, HRAS, KRAS, MAP2K1, NRAS
Signaling by high-kinase activity BRAF mutants	5	132.2×	3e-09	BRAF, HRAS, KRAS, MAP2K1, NRAS
Signaling by FGFR1 in disease	5	122.0×	4e-09	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
MAP2K and MAPK activation	5	119.0×	4e-09	BRAF, HRAS, KRAS, MAP2K1, NRAS
Signaling by RAF1 mutants	5	116.1×	5e-09	BRAF, HRAS, KRAS, MAP2K1, NRAS
Signaling by FGFR2 in disease	5	110.7×	6e-09	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
Negative regulation of MAPK pathway	5	110.7×	6e-09	BRAF, HRAS, KRAS, MAP2K1, NRAS
Signaling by moderate kinase activity BRAF mutants	5	105.7×	6e-09	BRAF, HRAS, KRAS, MAP2K1, NRAS
Paradoxical activation of RAF signaling by kinase inactive BRAF	5	105.7×	6e-09	BRAF, HRAS, KRAS, MAP2K1, NRAS
Signaling downstream of RAS mutants	5	105.7×	6e-09	BRAF, HRAS, KRAS, MAP2K1, NRAS
Signaling by SCF-KIT	5	103.4×	7e-09	HRAS, KRAS, NRAS, PIK3CA, PIK3R1
Signaling by RAS GAP mutants	3	951.7×	9e-09	HRAS, KRAS, NRAS
Signaling by RAS GTPase mutants	3	951.7×	9e-09	HRAS, KRAS, NRAS
Signaling by BRAF and RAF1 fusions	5	71.0×	4e-08	BRAF, HRAS, KRAS, MAP2K1, NRAS

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
MAPK cascade	5	63.8×	2e-06	BRAF, HRAS, KRAS, MAP2K1, NRAS
insulin-like growth factor receptor signaling pathway	3	123.9×	2e-04	MAP2K1, PIK3CA, PIK3R1
negative regulation of neuron apoptotic process	4	37.0×	3e-04	BRAF, HRAS, KRAS, PIK3CA
substrate adhesion-dependent cell spreading	3	86.0×	3e-04	BRAF, TEK, PIK3R1
positive regulation of ERK1 and ERK2 cascade	4	28.4×	4e-04	BRAF, TEK, HRAS, MAP2K1
insulin receptor signaling pathway	3	55.4×	8e-04	HRAS, PIK3CA, PIK3R1
Ras protein signal transduction	3	51.4×	9e-04	HRAS, KRAS, NRAS
Schwann cell development	2	175.5×	0.002	HRAS, MAP2K1
regulation of long-term neuronal synaptic plasticity	2	165.2×	0.002	HRAS, KRAS
T cell receptor signaling pathway	3	38.0×	0.002	BRAF, HRAS, PIK3CA
regulation of neurotransmitter receptor localization to postsynaptic specialization membrane	2	147.8×	0.002	HRAS, MAP2K1
face development	2	133.8×	0.002	BRAF, MAP2K1
positive regulation of Rac protein signal transduction	2	108.0×	0.003	TEK, KRAS
positive regulation of lamellipodium assembly	2	100.3×	0.003	PIK3CA, PIK3R1
positive regulation of Rho protein signal transduction	2	96.8×	0.003	TEK, MCF2L
positive regulation of axonogenesis	2	96.8×	0.003	BRAF, MAP2K1
thyroid gland development	2	90.6×	0.003	BRAF, MAP2K1
negative regulation of endothelial cell apoptotic process	2	82.6×	0.004	BRAF, TEK
phosphatidylinositol phosphate biosynthetic process	2	80.2×	0.004	PIK3CA, PIK3R1
adipose tissue development	2	66.9×	0.005	HRAS, PIK3CA
heart development	3	19.7×	0.005	TEK, GNA11, MAP2K1
response to muscle inactivity	1	1404.3×	0.006	PIK3CA
regulation of melanocyte differentiation	1	1404.3×	0.006	GNA11
response to mineralocorticoid	1	1404.3×	0.006	KRAS
response to butyrate	1	1404.3×	0.006	PIK3CA
thymus development	2	56.2×	0.006	BRAF, MAP2K1
positive regulation of smooth muscle cell proliferation	2	55.1×	0.006	PIK3CA, PIK3R1
response to glucocorticoid	2	54.0×	0.006	KRAS, MAP2K1
ERK1 and ERK2 cascade	2	53.0×	0.006	BRAF, MAP2K1
visual learning	2	51.1×	0.006	BRAF, KRAS

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Thalidomide	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Sirolimus.

Drug target analysis

Approved (phase 4): 9 · Phase ≥3: 9 · Phased (≥1): 10 · Undrugged: 2

Druggability breadth: 12 of 12 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
PIK3CA	IDELALISIB
BRAF	VEMURAFENIB
TEK	CETIRIZINE
CCNH	ABEMACICLIB
HRAS	LONAFARNIB
IDH2	ENASIDENIB
KRAS	VEMURAFENIB
MAP2K1	VEMURAFENIB
PIK3R1	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3CA	67	4
MAP2K1	54	4
BRAF	48	4
TEK	46	4
CCNH	28	4
PIK3R1	26	4
KRAS	11	4
IDH2	7	4
HRAS	4	4
NRAS	1	1

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDELALISIB	4	PIK3CA, PIK3R1
ALPELISIB	4	PIK3CA, PIK3R1
DUVELISIB	4	PIK3CA, PIK3R1
COPANLISIB	4	PIK3CA, PIK3R1
FEDRATINIB	4	BRAF, MAP2K1, PIK3CA, TEK
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	MAP2K1, PIK3CA
DASATINIB	4	BRAF, MAP2K1, PIK3CA
CRIZOTINIB	4	PIK3CA, TEK
MIDOSTAURIN	4	PIK3CA, TEK
VEMURAFENIB	4	BRAF, KRAS, MAP2K1
PONATINIB	4	BRAF
SORAFENIB	4	BRAF, MAP2K1, TEK
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF, MAP2K1
INFIGRATINIB PHOSPHATE	4	BRAF, TEK
INFIGRATINIB	4	BRAF, TEK
REGORAFENIB	4	BRAF, TEK
DABRAFENIB	4	BRAF, KRAS
COBIMETINIB	4	BRAF, MAP2K1
NILOTINIB	4	BRAF, TEK
ABEMACICLIB	4	BRAF, CCNH
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF, TEK
ERLOTINIB	4	BRAF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 8.

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
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
MAP2K1	1,200	Binding:1150, Functional:47, ADMET:3
KRAS	861	Binding:829, Functional:32
TEK	707	Binding:701, Functional:4, ADMET:2
PIK3R1	493	Binding:470, ADMET:23
CCNH	348	Binding:346, Functional:2
IDH2	84	Binding:84
HRAS	48	Binding:45, Functional:3
GNA11	18	Binding:18
NRAS	18	Binding:18
MCF2L	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
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
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
TEK	2.7.10.1	receptor protein-tyrosine kinase
HRAS	3.6.5.2	small monomeric GTPase
IDH2	1.1.1.42	isocitrate dehydrogenase (NADP+)
KRAS	3.6.5.2	small monomeric GTPase
MAP2K1	2.7.12.2	mitogen-activated protein kinase kinase
PIK3R1	2.7.1.153	phosphatidylinositol-4,5-bisphosphate 3-kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PIK3CA	2,034
BRAF	1,442
TEK	707
CCNH	348
KRAS	861
MAP2K1	1,200
PIK3R1	493

Pharmacogenomics

Cohort genes with a PharmGKB record: 12; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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)
IDELALISIB	4	PIK3CA, PIK3R1
DUVELISIB	4	PIK3CA, PIK3R1
COPANLISIB	4	PIK3CA, PIK3R1
FEDRATINIB	4	BRAF, MAP2K1, PIK3CA, TEK
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	MAP2K1, PIK3CA
DASATINIB	4	BRAF, MAP2K1, PIK3CA
CRIZOTINIB	4	PIK3CA, TEK
MIDOSTAURIN	4	PIK3CA, TEK
VEMURAFENIB	4	BRAF, KRAS, MAP2K1
PONATINIB	4	BRAF
SORAFENIB	4	BRAF, MAP2K1, TEK
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF, MAP2K1
INFIGRATINIB PHOSPHATE	4	BRAF, TEK
INFIGRATINIB	4	BRAF, TEK
REGORAFENIB	4	BRAF, TEK
DABRAFENIB	4	BRAF, KRAS
COBIMETINIB	4	BRAF, MAP2K1
NILOTINIB	4	BRAF, TEK
ABEMACICLIB	4	BRAF, CCNH
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF, TEK
ERLOTINIB	4	BRAF

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	9	PIK3CA, BRAF, TEK, CCNH, HRAS, IDH2, KRAS, MAP2K1, PIK3R1
B	Phased (≥1) drug, not yet approved	1	NRAS
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MCF2L, GNA11

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GNA11	18	BRAF, NRAS
MCF2L	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 38.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	23
PHASE2	10
PHASE3	4
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04999618	PHASE4	COMPLETED	A New Approach in Laser Surgery Using the Regenerative Solution in Children Diagnosed With Vascular Pathology
NCT02638389	PHASE3	RECRUITING	Efficacy and Safety of Sirolimus in Vascular Anomalies That Are Refractory to Standard Care
NCT02384122	PHASE3	COMPLETED	Efficacy of Octreotide on Blood and Iron Requirements in Patients With Anemia Due to Angiodysplasias
NCT03110783	PHASE3	COMPLETED	Bioseal Dural Sealing Study BIOS-14-001
NCT03987152	PHASE3	UNKNOWN	Treatment of Congenital Vascular Malformations Using Sirolimus: Improving Quality of Life
NCT05983159	PHASE2	RECRUITING	A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations
NCT06788314	PHASE2	RECRUITING	A Study of Enalapril in Treatment of Venous Malformations
NCT06789913	PHASE2	RECRUITING	A Phase 2 Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, in Adults and Children With PIK3CA Related Overgrowth Spectrum and Malformations Driven by PIK3CA Mutation
NCT07037238	PHASE2	RECRUITING	An Open-Label, Single-Arm Exploratory Clinical Study of Everolimus for the Treatment of Vascular Malformations
NCT07477548	PHASE2	NOT_YET_RECRUITING	A Study to Evaluate the Efficacy and Safety of Everolimus in Patients With Teratment-refractory Vascular Anomalies
NCT07579962	PHASE2	NOT_YET_RECRUITING	Treatment of Low-flow Vascular Malformations With Bleomycin Electrosclerotherapy (BEST)
NCT02509468	PHASE2	COMPLETED	suPERficial Slow-flow Vascular malFORMations Treated With sirolimUS
NCT02754960	PHASE2	WITHDRAWN	Efficacy Study of Thalidomide in Gastrointestinal Vascular Malformation Related Bleeding
NCT02883023	PHASE2	UNKNOWN	Electrosclerotherapy for Capillary Malformations
NCT03972592	PHASE2	COMPLETED	Topical Sirolimus in Cutaneous Lymphatic Malformations
NCT00833599	Not specified	ENROLLING_BY_INVITATION	Imaging Lymphatic Function in Normal Subjects and in Persons With Lymphatic Disorders
NCT04104464	Not specified	RECRUITING	Patient Reported Outcomes for Vascular Malformations EmbolizatioN (PROVEN)
NCT04189172	Not specified	ACTIVE_NOT_RECRUITING	MiDura-Study (Neuro-Patch in Duraplasty)
NCT05418816	Not specified	ACTIVE_NOT_RECRUITING	SelfWrap-Assisted Arteriovenous Fistulas
NCT06189092	Not specified	RECRUITING	Treatment of Low-flow Venous Malformations With Electrosclerotherapy. Prospective Observational Study
NCT06259292	Not specified	RECRUITING	Comprehensive HHT Outcomes Registry of the United States (CHORUS)
NCT06399367	Not specified	ENROLLING_BY_INVITATION	Investigation of Lipedema, Lymphedema and Vascular Malformations by Multispectral Optoacoustic Tomography (MSOT)
NCT06986954	Not specified	RECRUITING	Beacon Tip Sizing Catheter and Slip-Cath Beacon Tip Catheter Study
NCT06994260	Not specified	NOT_YET_RECRUITING	Diagnostic Imaging of Vascular Malformations Using MSOT and ULM
NCT07404670	Not specified	NOT_YET_RECRUITING	Microwave Ablation for Treatment of Vascular Malformations: Efficacy and Safety
NCT00577213	Not specified	COMPLETED	Diagnosis of Hemangiomas and Vascular Malformations
NCT01576601	Not specified	COMPLETED	The Management of Postoperative Craniotomy Pain in Pediatric Patients
NCT02250456	Not specified	UNKNOWN	AVAST Anomalies Vasculaires Associées au Syndrome de Turner (Vascular Abnormalities Associated With Turner Syndrome)
NCT02561182	Not specified	COMPLETED	Bone Health in Patients With Overgrowth
NCT02991352	Not specified	COMPLETED	Stereotactic MRI Based Image Guidance for the Treatment of Vascular Malformations - a Pilot Study
NCT03440827	Not specified	UNKNOWN	Development of a Specific Scale of Life’Quality for Children With Low-flow Vascular Malformations
NCT04637997	Not specified	COMPLETED	Influence of Flat-knitted Compression Stockings Class I and II on Venous Malformations
NCT04836884	Not specified	COMPLETED	Vascular Anomaly Pathology and Genomics Biopsy Study
NCT05113420	Not specified	UNKNOWN	The Efficacy and Safety of Different Phlebotonic Drugs in Children With Venous Malformations
NCT05494710	Not specified	UNKNOWN	Bleomycin Electrosclerotherapy Treatment of Vascular Malformations: A Feasibility Study
NCT05563831	Not specified	COMPLETED	National Evaluation of Patients With PIK3CA-Related Overgrowth Spectrum (PROS)
NCT06160739	Not specified	UNKNOWN	Role of Sirolimus in Treatment of Microcystic , Mixed Lymphatic and Vascular Malformations
NCT07320430	Not specified	COMPLETED	Comparative Study Between Sclerosing Agents Used in Treatment of Vascular Malformation

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BLEOMYCIN	4	3
ENALAPRIL	4	3
ALPELISIB	4	1
OCTREOTIDE	4	1
MIRDAMETINIB	2	1
RLY-2608	1	1
CHEMBL3350037	0	1

Cohort genes: MCF2L, PIK3CA, BRAF, TEK, CCNH, GNA11, HRAS, IDH2, KRAS, MAP2K1, NRAS, PIK3R1
Drugs: Bleomycin, Enalapril, Alpelisib, Octreotide