Is EPHB4 p.Ala453Val (c.1358C>T) pathogenic?

EPHB4 p.Ala453Val (c.1358C>T) is classified Likely benign in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-17). AlphaMissense: likely benign (0.1434); Very rare (popmax 0.00415%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Ala453Val (c.1358C>T)?

EPHB4 p.Ala453Val (c.1358C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Ala453Val (c.1358C>T) in the general population?

EPHB4 p.Ala453Val (c.1358C>T) is very rare (popmax 0.00415%, nfe) (gnomAD).

What do computational predictors say about EPHB4 p.Ala453Val (c.1358C>T)?

AlphaMissense predicts likely benign (score 0.1434) — an in-silico prediction, not a clinical call.

EPHB4 p.Ala453Val

c.1358C>T · rs150425369 · VCV1770739

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1434 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00415%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1434	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -7.15	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 4.4	GERP 2.2, phastCons 0.99
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	21.9	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 0.00415% European (non-Finnish) · 49/1,180,038 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00322% 52/1,613,620 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00415%	24,082
East Asian	0.00223%	44,886
Remaining individualsnot grpmax-eligible	0.0016%	62,476
African / African-American	0.00133%	74,938

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.Ala453Val
Coding: c.1358C>T
MANE Select: NM_004444
dbSNP: rs150425369
Type: single nucleotide variant
Location: chr7:100818584 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 453: a β-strand; 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.Ala453Thr 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-ala453val (accessed [today's date]).

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