Capillary malformation-arteriovenous malformation 2

Summary

Capillary malformation-arteriovenous malformation 2 (MONDO:0020785) is a disease caused by EPHB4 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: EPHB4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 95

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	capillary malformation-arteriovenous malformation 2
Mondo ID	MONDO:0020785
OMIM	618196
Orphanet	693912
UMLS	C4748670
MedGen	1648502
GARD	0016307
Is cancer (heuristic)	no

Also known as: CMAVM2

Data availability: 95 ClinVar variants · 4 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 2

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

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

95 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 23 likely pathogenic, 18 conflicting classifications of pathogenicity, 14 pathogenic, 6 pathogenic/likely pathogenic, 5 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1324340	NM_004444.5(EPHB4):c.1738C>T (p.Gln580Ter)	EPHB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1426188	NM_004444.5(EPHB4):c.1039dup (p.Leu347fs)	EPHB4	Pathogenic	criteria provided, multiple submitters, no conflicts
1678587	NM_004444.5(EPHB4):c.2287C>T (p.Arg763Ter)	EPHB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1678591	NM_004444.5(EPHB4):c.1093C>T (p.Arg365Ter)	EPHB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1704386	NM_004444.5(EPHB4):c.2215C>T (p.Arg739Ter)	EPHB4	Pathogenic	criteria provided, multiple submitters, no conflicts
1806103	NM_004444.5(EPHB4):c.1788T>A (p.Tyr596Ter)	EPHB4	Pathogenic	criteria provided, single submitter
1806264	NM_004444.5(EPHB4):c.216G>A (p.Trp72Ter)	EPHB4	Pathogenic	criteria provided, single submitter
3255221	NM_004444.5(EPHB4):c.2389_2392del (p.Phe797fs)	EPHB4	Pathogenic	criteria provided, single submitter
3774492	NM_004444.5(EPHB4):c.27_33dup (p.Leu12fs)	EPHB4	Pathogenic	criteria provided, single submitter
590870	NM_004444.5(EPHB4):c.33del (p.Leu12fs)	EPHB4	Pathogenic	no assertion criteria provided
590872	NM_004444.5(EPHB4):c.632_633del (p.Val211fs)	EPHB4	Pathogenic	criteria provided, single submitter
590873	NM_004444.5(EPHB4):c.1990G>A (p.Glu664Lys)	EPHB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
590874	NM_004444.5(EPHB4):c.2484+1G>A	EPHB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
590875	NM_004444.5(EPHB4):c.2484+1G>T	EPHB4	Pathogenic	no assertion criteria provided
590877	NM_004444.5(EPHB4):c.570dup (p.His191fs)	EPHB4	Pathogenic	no assertion criteria provided
620197	NM_004444.5(EPHB4):c.2418C>G (p.Tyr806Ter)	EPHB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
691531	NM_004444.5(EPHB4):c.389G>A (p.Trp130Ter)	EPHB4	Pathogenic	criteria provided, single submitter
691537	NM_004444.5(EPHB4):c.1123G>T (p.Gly375Ter)	EPHB4	Pathogenic	criteria provided, single submitter
1164042	NM_004444.5(EPHB4):c.2605dup (p.Gln869fs)	LOC126860124	Pathogenic	no assertion criteria provided
4819582	NM_004444.5(EPHB4):c.2424_2425insA (p.Val809fs)	LOC126860124	Pathogenic	criteria provided, single submitter
1324339	NM_004444.5(EPHB4):c.1124dup (p.Asp376fs)	EPHB4	Likely pathogenic	criteria provided, single submitter
1339263	NM_004444.5(EPHB4):c.1861_1864dup (p.Gly622fs)	EPHB4	Likely pathogenic	criteria provided, single submitter
1342553	NM_004444.5(EPHB4):c.2044G>A (p.Val682Met)	EPHB4	Likely pathogenic	criteria provided, single submitter
1678612	NM_004444.5(EPHB4):c.1153dup (p.Asp385fs)	EPHB4	Likely pathogenic	criteria provided, single submitter
1678623	NM_004444.5(EPHB4):c.410A>T (p.Lys137Met)	EPHB4	Likely pathogenic	criteria provided, single submitter
1691321	NM_004444.5(EPHB4):c.1541G>A (p.Gly514Asp)	EPHB4	Likely pathogenic	criteria provided, single submitter
1698833	NM_004444.5(EPHB4):c.2420G>A (p.Gly807Glu)	EPHB4	Likely pathogenic	criteria provided, single submitter
1806256	NM_004444.5(EPHB4):c.964+3A>T	EPHB4	Likely pathogenic	criteria provided, single submitter
2502842	NM_004444.5(EPHB4):c.2197G>T (p.Glu733Ter)	EPHB4	Likely pathogenic	no assertion criteria provided
2579685	NM_004444.5(EPHB4):c.732dup (p.Trp245fs)	EPHB4	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 4 · 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
EPHB4	Definitive	Autosomal dominant	EPHB4-associated vascular malformation spectrum	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EPHB4	Orphanet:1053	Vein of Galen malformation
EPHB4	Orphanet:568065	EPHB4-related lymphatic-related hydrops fetalis
EPHB4	Orphanet:693912	EPHB4-related capillary malformation-arteriovenous malformation
EPHB4	Orphanet:90186	Meige disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EPHB4	HGNC:3395	ENSG00000196411	P54760	Ephrin type-B receptor 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EPHB4	Ephrin type-B receptor 4	Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EPHB4	Kinase	yes	2.7.10.1	Prot_kinase_dom, EPH_LBD, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of uterus	1
olfactory bulb	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EPHB4	282	ubiquitous	marker	olfactory bulb, type B pancreatic cell, body of uterus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EPHB4	2,547

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EPHB4	P54760	23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Ephrin signaling	1	571.0×	0.006	EPHB4
EPHB-mediated forward signaling	1	265.6×	0.006	EPHB4
EPH-ephrin mediated repulsion of cells	1	219.6×	0.006	EPHB4
EPH-Ephrin signaling	1	165.5×	0.006	EPHB4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cell migration involved in sprouting angiogenesis	1	648.1×	0.005	EPHB4
heart morphogenesis	1	374.5×	0.005	EPHB4
ephrin receptor signaling pathway	1	343.9×	0.005	EPHB4
angiogenesis	1	62.4×	0.020	EPHB4
cell adhesion	1	37.5×	0.027	EPHB4

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 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
EPHB4	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EPHB4	46	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	EPHB4
FEDRATINIB	4	EPHB4
TIVOZANIB	4	EPHB4
SORAFENIB	4	EPHB4
DASATINIB ANHYDROUS	4	EPHB4
VANDETANIB	4	EPHB4
NILOTINIB	4	EPHB4
BOSUTINIB	4	EPHB4
TOVORAFENIB	4	EPHB4
NINTEDANIB	4	EPHB4
SUNITINIB	4	EPHB4
DASATINIB	4	EPHB4
ERLOTINIB	4	EPHB4
CRIZOTINIB	4	EPHB4
GEFITINIB	4	EPHB4
SARACATINIB	3	EPHB4
LINIFANIB	3	EPHB4
CANERTINIB	3	EPHB4
TESEVATINIB	3	EPHB4
POZIOTINIB	3	EPHB4
ALISERTIB	3	EPHB4
CEDIRANIB	3	EPHB4
LESTAURTINIB	3	EPHB4
DORAMAPIMOD	2	EPHB4
NEFLAMAPIMOD	2	EPHB4
FORETINIB	2	EPHB4
REBASTINIB	2	EPHB4
CEP-32496	2	EPHB4
BAFETINIB	2	EPHB4
SAPITINIB	2	EPHB4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
EPHB4	437	Binding:437

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EPHB4	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EPHB4	437

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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)
PONATINIB	4	EPHB4
FEDRATINIB	4	EPHB4
TIVOZANIB	4	EPHB4
SORAFENIB	4	EPHB4
DASATINIB ANHYDROUS	4	EPHB4
VANDETANIB	4	EPHB4
NILOTINIB	4	EPHB4
BOSUTINIB	4	EPHB4
TOVORAFENIB	4	EPHB4
NINTEDANIB	4	EPHB4
SUNITINIB	4	EPHB4
DASATINIB	4	EPHB4
ERLOTINIB	4	EPHB4
CRIZOTINIB	4	EPHB4
GEFITINIB	4	EPHB4
SARACATINIB	3	EPHB4
LINIFANIB	3	EPHB4
CANERTINIB	3	EPHB4
TESEVATINIB	3	EPHB4
POZIOTINIB	3	EPHB4
ALISERTIB	3	EPHB4
CEDIRANIB	3	EPHB4
LESTAURTINIB	3	EPHB4
DORAMAPIMOD	2	EPHB4
NEFLAMAPIMOD	2	EPHB4
FORETINIB	2	EPHB4
REBASTINIB	2	EPHB4
CEP-32496	2	EPHB4
BAFETINIB	2	EPHB4
SAPITINIB	2	EPHB4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	EPHB4
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.