Is EPHB4 p.Ala476Thr (c.1426G>A) pathogenic?

EPHB4 p.Ala476Thr (c.1426G>A) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely benign (0.0673); Very rare (popmax 0.00587%, sas); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Ala476Thr (c.1426G>A)?

EPHB4 p.Ala476Thr (c.1426G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Ala476Thr (c.1426G>A) in the general population?

EPHB4 p.Ala476Thr (c.1426G>A) is very rare (popmax 0.00587%, sas) (gnomAD).

What do computational predictors say about EPHB4 p.Ala476Thr (c.1426G>A)?

AlphaMissense predicts likely benign (score 0.0673) — an in-silico prediction, not a clinical call.

EPHB4 p.Ala476Thr

c.1426G>A · VCV4614147

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0673 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00587%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0673	likely benign
REVEL	0.005	strongly benign-leaning
SaProt	LLR -9.73	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 0.57	GERP -1.2, phastCons 0.093
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	13.84	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 0.00587% South Asian · 5/85,130 alleles

Filtering AF 0.00222% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00145%

Overall 0.000849% 12/1,412,940 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00587%	17,026
Remaining individualsnot grpmax-eligible	0.00165%	60,584
African / African-American	0.00136%	73,408
European (non-Finnish)	0.000432%	231,487

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.Ala476Thr
Coding: c.1426G>A
MANE Select: NM_004444
Type: single nucleotide variant
Location: chr7:100817354 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 476: 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

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

Similar variants

EPHB4 p.Ala476= Likely benign ★ same residue
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

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-ala476thr (accessed [today's date]).

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