Is EPHB4 p.Gly514Asp (c.1541G>A) pathogenic?

EPHB4 p.Gly514Asp (c.1541G>A) is classified Likely pathogenic in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-20). AlphaMissense: likely pathogenic (0.9889); Absent from gnomAD v4.1; Associated with capillary malformation-arteriovenous malformation 2.

What condition is associated with EPHB4 p.Gly514Asp (c.1541G>A)?

EPHB4 p.Gly514Asp (c.1541G>A) is associated with capillary malformation-arteriovenous malformation 2 (ClinVar).

How common is EPHB4 p.Gly514Asp (c.1541G>A) in the general population?

EPHB4 p.Gly514Asp (c.1541G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPHB4 p.Gly514Asp (c.1541G>A)?

AlphaMissense predicts likely pathogenic (score 0.9889) — an in-silico prediction, not a clinical call.

EPHB4 p.Gly514Asp

c.1541G>A · rs2116443777 · VCV1691321

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9889 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,601,912)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

capillary malformation-arteriovenous malformation 2

Computational evidence

Protein change
AlphaMissense	0.9889	likely pathogenic ✓ concordant with ClinVar
REVEL	0.752	pathogenic-leaning
SaProt	LLR -12.49	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,601,912). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: EPHB4
Protein: p.Gly514Asp
Coding: c.1541G>A
MANE Select: NM_004444
dbSNP: rs2116443777
Type: single nucleotide variant
Location: chr7:100817239 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 514: a UniProt-annotated variant site (in cmavm2); the fibronectin type-iii 2 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 p.Gly514Ser Uncertain significance ★★ ⚠ same residue
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

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-gly514asp (accessed [today's date]).

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