Capillary malformation

Summary

Capillary malformation (MONDO:0016231) is a disease (an umbrella term covering 6 Mondo subtypes) with 4 cohort genes and 4 clinical trials. The dominant Reactome pathway is High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells (3 cohort genes). Top therapeutic interventions include brimonidine.

At a glance

• Umbrella term: 6 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 7
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	capillary malformation
Mondo ID	MONDO:0016231
Orphanet	211247
SNOMED CT	234118009
UMLS	C0340803
MedGen	90955
Is cancer (heuristic)	no

Also known as: congenital malformation of capillary

Data availability: 7 ClinVar variants.

Disease family

An umbrella term covering 6 Mondo subtypes.

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

Related subtypes (59): arterial disorder, ischemic colitis, thrombotic disease, capillary disorder, angiodysplasia, hepatic vascular disorder, vascular hemostatic disease, vein disorder, ischemic disease, peripheral vascular disease, venous thromboembolism, ocular vascular disorder, cholesterol embolism, thoracic outlet syndrome, idiopathic spontaneous coronary artery dissection, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, angioosteohypertrophic syndrome, Bannayan-Riley-Ruvalcaba syndrome, arterial tortuosity syndrome, hereditary arterial and articular multiple calcification syndrome, pulmonary venoocclusive disease, multiple cutaneous and mucosal venous malformations, arterial dissection-lentiginosis syndrome, patent ductus arteriosus, multisystemic smooth muscle dysfunction syndrome, STING-associated vasculopathy with onset in infancy, Ehlers-Danlos syndrome, vascular-like type, calciphylaxis, neonatal Marfan syndrome, Ehlers-Danlos syndrome, vascular type, lethal arteriopathy syndrome due to fibulin-4 deficiency, congenital portosystemic shunt, arterial calcification of infancy, vasculitis, Loeys-Dietz syndrome, skin vascular disease, lymphatic malformation, familial thoracic aortic aneurysm and aortic dissection, congenital anomaly of superior vena cava, congenital anomaly of the inferior vena cava, congenital anomaly of hepatic vein, congenital renal artery stenosis, internal carotid agenesis, coronary sinus stenosis, coronary sinus atresia, vascular occlusion disorder, vascular insufficiency disorder, blood vessel neoplasm, vascular ectasia, vascular disorder of penis, fibrocartilaginous embolism, vascular malformation, lymphatic vessel neoplasm, neurovascular disorder, superior vena cava syndrome, coronary microvascular disorder, segmental arterial mediolysis, bleeding disorder, vascular-type, arterial tortuosity-bone fragility syndrome

Subtypes (6): stork bite, familial multiple nevi flammei, cutis marmorata telangiectatica congenita, capillary malformation-arteriovenous malformation syndrome, hereditary hemorrhagic telangiectasia, angioma serpiginosum

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

7 retrieved; paginated sample, class counts are floors:

4 pathogenic, 1 uncertain significance, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
3774521	NM_002890.3(RASA1):c.2476C>T (p.Gln826Ter)	CCNH	Pathogenic	criteria provided, single submitter
50853	NM_002072.5(GNAQ):c.548G>A (p.Arg183Gln)	GNAQ	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217293	NM_006218.4(PIK3CA):c.1635G>T (p.Glu545Asp)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
31945	NM_006218.4(PIK3CA):c.1258T>C (p.Cys420Arg)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
917489	NM_006218.4(PIK3CA):c.1132T>C (p.Cys378Arg)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
548668	NM_002067.5(GNA11):c.547C>T (p.Arg183Cys)	GNA11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4279973	NM_002890.3(RASA1):c.1064A>G (p.Lys355Arg)	CCNH	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
GNAQ	Orphanet:3205	Sturge-Weber syndrome
GNAQ	Orphanet:39044	Uveal melanoma
GNAQ	Orphanet:624	Familial multiple nevi flammei
GNAQ	Orphanet:675359	Anastomosing haemangioma
GNAQ	Orphanet:79483	Phakomatosis cesioflammea
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
CCNH	HGNC:1594	ENSG00000134480	P51946	Cyclin-H	clinvar
GNA11	HGNC:4379	ENSG00000088256	P29992	Guanine nucleotide-binding protein subunit alpha-11	clinvar
GNAQ	HGNC:4390	ENSG00000156052	P50148	Guanine nucleotide-binding protein G(q) subunit alpha	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)
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.
GNAQ	Guanine nucleotide-binding protein G(q) subunit alpha	Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.
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: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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×	0.273
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CCNH	Other/Unknown	no		Cyclin_N, Cyclin-like_dom, CyclinH/Ccl1
GNA11	Other/Unknown	no		Gprotein_alpha_Q, Gprotein_alpha_su, GproteinA_insert
GNAQ	Other/Unknown	no		Gprotein_alpha_Q, Gprotein_alpha_su, GproteinA_insert
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
left testis	1
right testis	1
ileal mucosa	1
jejunal mucosa	1
pancreatic ductal cell	1
CA1 field of hippocampus	1
dorsal motor nucleus of vagus nerve	1
postcentral gyrus	1
adrenal tissue	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CCNH	297	ubiquitous	marker	calcaneal tendon, left testis, right testis
GNA11	299	ubiquitous	marker	ileal mucosa, jejunal mucosa, pancreatic ductal cell
GNAQ	302	ubiquitous	marker	CA1 field of hippocampus, dorsal motor nucleus of vagus nerve, postcentral gyrus
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
PIK3CA	5,157
GNAQ	3,480
CCNH	2,116
GNA11	1,873

Intra-cohort edges

A	B	Sources
GNA11	GNAQ	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3CA	P42336	135
CCNH	P51946	47
GNAQ	P50148	37
GNA11	P29992	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 130. 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
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	3	120.6×	1e-04	GNA11, GNAQ, PIK3CA
Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion	2	713.8×	2e-04	GNA11, GNAQ
Acetylcholine regulates insulin secretion	2	571.0×	2e-04	GNA11, GNAQ
G-protein activation	2	237.9×	5e-04	GNA11, GNAQ
Thromboxane signalling through TP receptor	2	237.9×	5e-04	GNA11, GNAQ
ADP signalling through P2Y purinoceptor 1	2	228.4×	5e-04	GNA11, GNAQ
G alpha (q) signalling events	3	43.0×	5e-04	GNA11, GNAQ, PIK3CA
Thrombin signalling through proteinase activated receptors (PARs)	2	178.4×	7e-04	GNA11, GNAQ
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	2	178.4×	7e-04	GNA11, GNAQ
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding	2	150.3×	8e-04	GNA11, GNAQ
PLC beta mediated events	2	132.8×	1e-03	GNA11, GNAQ
MET activates PI3K/AKT signaling	1	475.8×	0.021	PIK3CA
Activated NTRK3 signals through PI3K	1	475.8×	0.021	PIK3CA
Activated NTRK2 signals through PI3K	1	407.9×	0.021	PIK3CA
Signaling by LTK in cancer	1	407.9×	0.021	PIK3CA
PI3K/AKT activation	1	317.2×	0.025	PIK3CA
IRS-mediated signalling	1	259.6×	0.025	PIK3CA
PI3K events in ERBB4 signaling	1	259.6×	0.025	PIK3CA
Co-stimulation by ICOS	1	259.6×	0.025	PIK3CA
Signaling by FGFR4 in disease	1	237.9×	0.025	PIK3CA
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	237.9×	0.025	PIK3CA
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	219.6×	0.025	PIK3CA
Signaling by PDGFRA extracellular domain mutants	1	219.6×	0.025	PIK3CA
Signaling by LTK	1	219.6×	0.025	PIK3CA
Signaling by FLT3 ITD and TKD mutants	1	190.3×	0.025	PIK3CA
Constitutive Signaling by EGFRvIII	1	178.4×	0.025	PIK3CA
PI3K events in ERBB2 signaling	1	167.9×	0.025	PIK3CA
Signaling by ERBB2 ECD mutants	1	167.9×	0.025	PIK3CA
GAB1 signalosome	1	158.6×	0.025	PIK3CA
Signaling by cytosolic FGFR1 fusion mutants	1	158.6×	0.025	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
entrainment of circadian clock	2	1404.3×	5e-05	GNA11, GNAQ
phototransduction, visible light	2	648.1×	1e-04	GNA11, GNAQ
G protein-coupled acetylcholine receptor signaling pathway	2	526.6×	1e-04	GNA11, GNAQ
response to muscle inactivity	1	4213.0×	0.003	PIK3CA
regulation of melanocyte differentiation	1	4213.0×	0.003	GNA11
response to butyrate	1	4213.0×	0.003	PIK3CA
phospholipase C-activating G protein-coupled receptor signaling pathway	2	65.8×	0.004	GNA11, GNAQ
response to L-leucine	1	1404.3×	0.007	PIK3CA
cellular response to hydrostatic pressure	1	1404.3×	0.007	PIK3CA
phospholipase C-activating G protein-coupled glutamate receptor signaling pathway	1	1053.2×	0.007	GNAQ
phospholipase C-activating serotonin receptor signaling pathway	1	702.2×	0.007	GNAQ
regulation of platelet activation	1	702.2×	0.007	GNAQ
negative regulation of actin filament depolymerization	1	702.2×	0.007	PIK3CA
regulation of cellular respiration	1	702.2×	0.007	PIK3CA
regulation of actin filament organization	1	601.9×	0.007	PIK3CA
autosome genomic imprinting	1	601.9×	0.007	PIK3CA
negative regulation of fibroblast apoptotic process	1	601.9×	0.007	PIK3CA
phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway	1	526.6×	0.007	GNA11
developmental pigmentation	1	526.6×	0.007	GNA11
phospholipase C-activating dopamine receptor signaling pathway	1	526.6×	0.007	GNA11
cellular response to pH	1	526.6×	0.007	GNA11
protein stabilization	2	33.4×	0.007	CCNH, GNAQ
sensory perception of itch	1	468.1×	0.007	GNAQ
ligand-gated ion channel signaling pathway	1	468.1×	0.007	GNA11
cardiac muscle cell contraction	1	421.3×	0.007	PIK3CA
endothelin receptor signaling pathway	1	421.3×	0.007	GNA11
positive regulation of protein localization to membrane	1	421.3×	0.007	PIK3CA
TORC2 signaling	1	383.0×	0.008	PIK3CA
response to prostaglandin E	1	351.1×	0.008	GNAQ
phosphatidylinositol-3-phosphate biosynthetic process	1	324.1×	0.008	PIK3CA

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 4 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
CCNH	ABEMACICLIB
PIK3CA	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3CA	67	4
CCNH	28	4
GNA11	0	0
GNAQ	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ABEMACICLIB	4	CCNH
QUIZARTINIB	4	CCNH
ADAGRASIB	4	CCNH
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
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	PIK3CA
TASELISIB	3	PIK3CA
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	PIK3CA
SELICICLIB	2	CCNH
ASNUCICLIB	2	CCNH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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
CCNH	348	Binding:346, Functional:2
GNAQ	27	Binding:27
GNA11	18	Binding:18

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

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CCNH	348
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
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
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	PIK3CA
TASELISIB	3	PIK3CA
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	PIK3CA
SELICICLIB	2	CCNH
ASNUCICLIB	2	CCNH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CCNH, 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	2	GNA11, GNAQ

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	—
GNAQ	27	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE3	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02764411	PHASE3	TERMINATED	Onreltea (Brimonidine) Gel In Pediatric Patients With Capillary Malformations
NCT02883023	PHASE2	UNKNOWN	Electrosclerotherapy for Capillary Malformations
NCT01735734	Not specified	UNKNOWN	Assessing the Effects of Air-cooling on Capillary Malformations
NCT02035319	Not specified	WITHDRAWN	Effect of Laser Treatment on Capillary Malformations

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BRIMONIDINE	4	4