Is EPHB4 p.Val753Ile (c.2257G>A) pathogenic?

EPHB4 p.Val753Ile (c.2257G>A) is classified Likely benign in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-05). AlphaMissense: ambiguous (0.3618); Ultra-rare (popmax 0.045%, sas); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Val753Ile (c.2257G>A)?

EPHB4 p.Val753Ile (c.2257G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Val753Ile (c.2257G>A) in the general population?

EPHB4 p.Val753Ile (c.2257G>A) is ultra-rare (popmax 0.045%, sas) (gnomAD).

What do computational predictors say about EPHB4 p.Val753Ile (c.2257G>A)?

AlphaMissense predicts ambiguous (score 0.3618) — an in-silico prediction, not a clinical call.

EPHB4 p.Val753Ile

c.2257G>A · rs368484374 · VCV1788539

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3618 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3618	ambiguous
REVEL	0.371	indeterminate
SaProt	LLR -8.84	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 6,734 bp · p 5.4e-12 · regional, not allelic
Overall
CADD	29.0	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 0.045% South Asian · 41/91,080 alleles

Filtering AF 0.034% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.00366% 59/1,613,772 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.045%	2,221
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0016%	62,478
African / African-American	0.00134%	74,826
European (non-Finnish)	0.00127%	78,668

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.Val753Ile
Coding: c.2257G>A
MANE Select: NM_004444
dbSNP: rs368484374
Type: single nucleotide variant
Location: chr7:100807442 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 753: a UniProt-annotated variant site (in cmavm2); the protein kinase domain

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPHB4 c.1870+5G>C Uncertain significance ★★ same condition
EPHB4 p.Ala262Val Uncertain significance ★★ ⚠ same condition
EPHB4 p.Ala345Gly Uncertain significance ★★ ⚠ same condition
EPHB4 p.Ala931Thr Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg148Trp Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg310Gln Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg483Gln Uncertain significance ★★ ⚠ same condition
EPHB4 p.Arg499Gln 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-val753ile (accessed [today's date]).

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