Is EPHB4 p.Cys370Phe (c.1109G>T) pathogenic?

EPHB4 p.Cys370Phe (c.1109G>T) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-18). AlphaMissense: likely pathogenic (0.936); Very rare (popmax 0.00134%, afr); Associated with capillary malformation-arteriovenous malformation 2.

What condition is associated with EPHB4 p.Cys370Phe (c.1109G>T)?

EPHB4 p.Cys370Phe (c.1109G>T) is associated with capillary malformation-arteriovenous malformation 2 (ClinVar).

How common is EPHB4 p.Cys370Phe (c.1109G>T) in the general population?

EPHB4 p.Cys370Phe (c.1109G>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about EPHB4 p.Cys370Phe (c.1109G>T)?

AlphaMissense predicts likely pathogenic (score 0.936) — an in-silico prediction, not a clinical call.

EPHB4 p.Cys370Phe

c.1109G>T · rs1329211881 · VCV2582347

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

capillary malformation-arteriovenous malformation 2

Computational evidence

Protein change
AlphaMissense	0.936	likely pathogenic
REVEL	0.879	moderately pathogenic-leaning
SaProt	LLR -12.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 0.25, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,822 alleles

Overall 6.22e-05% 1/1,608,372 alleles · very rare exomes 0/1,456,110 · genomes 1/152,262 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EPHB4
Protein: p.Cys370Phe
Coding: c.1109G>T
MANE Select: NM_004444
dbSNP: rs1329211881
Type: single nucleotide variant
Location: chr7:100819745 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 370: a UniProt-annotated variant site (in cmavm2); the fibronectin type-iii 1 domain

Full EPHB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

capillary malformation-arteriovenous malformation 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPHB4 c.2484+1G>A Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg365Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Arg739Ter Pathogenic ★★ same condition
EPHB4 p.Arg763Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Gln580Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Glu664Lys Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Trp72Ter Pathogenic/Likely pathogenic ★★ same condition
EPHB4 p.Cys285Arg Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ephb4-p-cys370phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown