Is EPHB4 p.Ala262Val (c.785C>T) pathogenic?

EPHB4 p.Ala262Val (c.785C>T) is classified Uncertain significance in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-29). AlphaMissense: likely benign (0.0812); Very rare (popmax 0.00239%, eas); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Ala262Val (c.785C>T)?

EPHB4 p.Ala262Val (c.785C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Ala262Val (c.785C>T) in the general population?

EPHB4 p.Ala262Val (c.785C>T) is very rare (popmax 0.00239%, eas) (gnomAD).

What do computational predictors say about EPHB4 p.Ala262Val (c.785C>T)?

AlphaMissense predicts likely benign (score 0.0812) — an in-silico prediction, not a clinical call.

EPHB4 p.Ala262Val

c.785C>T · rs768458157 · VCV2626719

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0812 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00239%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0812	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -6.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.86 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.7	GERP -1, phastCons 0.58
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	11.38	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00239% East Asian · 1/41,786 alleles

Filtering AF 0.000252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000162%

Overall 0.000575% 9/1,564,080 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00239%	41,786
Remaining individualsnot grpmax-eligible	0.00165%	60,424
European (non-Finnish)	0.000607%	164,748

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.Ala262Val
Coding: c.785C>T
MANE Select: NM_004444
dbSNP: rs768458157
Type: single nucleotide variant
Location: chr7:100822294 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 262: a UniProt-annotated variant site (in cmavm2)

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.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
EPHB4 p.Arg535Trp 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-ala262val (accessed [today's date]).

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