Is EPHB4 p.Glu117Asp (c.351G>C) pathogenic?

EPHB4 p.Glu117Asp (c.351G>C) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-25). AlphaMissense: likely pathogenic (0.9186); Very rare (popmax 0.000254%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Glu117Asp (c.351G>C)?

EPHB4 p.Glu117Asp (c.351G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Glu117Asp (c.351G>C) in the general population?

EPHB4 p.Glu117Asp (c.351G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about EPHB4 p.Glu117Asp (c.351G>C)?

AlphaMissense predicts likely pathogenic (score 0.9186) — an in-silico prediction, not a clinical call.

EPHB4 p.Glu117Asp

c.351G>C · rs767722877 · VCV1732254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9186 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9186	likely pathogenic
REVEL	0.243	benign-leaning
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.21	GERP 1.3, phastCons 0.97
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	21.8	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 0.000254% European (non-Finnish) · 3/1,179,984 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,484 alleles · very rare

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.Glu117Asp
Coding: c.351G>C
MANE Select: NM_004444
dbSNP: rs767722877
Type: single nucleotide variant
Location: chr7:100823704 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 117: a disulfide bond; the eph lbd domain; a β-strand

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.Glu117= 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-glu117asp (accessed [today's date]).

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