Is EPHB4 p.Gly519Ser (c.1555G>A) pathogenic?

EPHB4 p.Gly519Ser (c.1555G>A) is classified Conflicting classifications of pathogenicity in EPHB4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-10). AlphaMissense: likely benign (0.1557); Ultra-rare (popmax 0.014%, amr); Associated with capillary malformation-arteriovenous malformation 2.

What condition is associated with EPHB4 p.Gly519Ser (c.1555G>A)?

EPHB4 p.Gly519Ser (c.1555G>A) is associated with capillary malformation-arteriovenous malformation 2 (ClinVar).

How common is EPHB4 p.Gly519Ser (c.1555G>A) in the general population?

EPHB4 p.Gly519Ser (c.1555G>A) is ultra-rare (popmax 0.014%, amr) (gnomAD).

What do computational predictors say about EPHB4 p.Gly519Ser (c.1555G>A)?

AlphaMissense predicts likely benign (score 0.1557) — an in-silico prediction, not a clinical call.

EPHB4 p.Gly519Ser

c.1555G>A · rs761047725 · VCV1985154

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1557 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.014%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

capillary malformation-arteriovenous malformation 2

Computational evidence

Protein change
AlphaMissense	0.1557	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -1.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.92, phastCons 0.97
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	17.14	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

Grpmax group 0.014% Admixed American · 8/57,274 alleles

Filtering AF 0.00689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00502%

Overall 0.00151% 24/1,591,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.014%	7,159
South Asian	0.0102%	9,808
African / African-American	0.00545%	18,363
East Asian	0.00236%	42,436
European (non-Finnish)	0.000171%	584,583

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.Gly519Ser
Coding: c.1555G>A
MANE Select: NM_004444
dbSNP: rs761047725
Type: single nucleotide variant
Location: chr7:100817225 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 519: 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 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-gly519ser (accessed [today's date]).

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