Is EPHB4 p.Ala83Thr (c.247G>A) pathogenic?

EPHB4 p.Ala83Thr (c.247G>A) is classified Conflicting classifications of pathogenicity in EPHB4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-05-30). AlphaMissense: ambiguous (0.4469); Very rare (popmax 0.00288%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Ala83Thr (c.247G>A)?

EPHB4 p.Ala83Thr (c.247G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Ala83Thr (c.247G>A) in the general population?

EPHB4 p.Ala83Thr (c.247G>A) is very rare (popmax 0.00288%, nfe) (gnomAD).

What do computational predictors say about EPHB4 p.Ala83Thr (c.247G>A)?

AlphaMissense predicts ambiguous (score 0.4469) — an in-silico prediction, not a clinical call.

EPHB4 p.Ala83Thr

c.247G>A · rs371690893 · VCV2662598

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4469 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4469	ambiguous
REVEL	0.307	indeterminate
SaProt	LLR -8.40	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	25.8	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 0.00288% European (non-Finnish) · 34/1,179,908 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00229% 37/1,612,988 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00288%	34,703
Admixed American	0.00167%	59,988
Finnishnot grpmax-eligible	0.00158%	63,184
African / African-American	0.00133%	74,936

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.Ala83Thr
Coding: c.247G>A
MANE Select: NM_004444
dbSNP: rs371690893
Type: single nucleotide variant
Location: chr7:100823808 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 83: a disulfide bond; the eph lbd 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.Ala83= 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-ala83thr (accessed [today's date]).

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