Is EPHB4 p.Gly893Arg (c.2677G>A) pathogenic?

EPHB4 p.Gly893Arg (c.2677G>A) is classified Likely benign in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-28). AlphaMissense: ambiguous (0.4126); Rare (popmax 0.107%, afr); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Gly893Arg (c.2677G>A)?

EPHB4 p.Gly893Arg (c.2677G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Gly893Arg (c.2677G>A) in the general population?

EPHB4 p.Gly893Arg (c.2677G>A) is rare (popmax 0.107%, afr) (gnomAD).

What do computational predictors say about EPHB4 p.Gly893Arg (c.2677G>A)?

AlphaMissense predicts ambiguous (score 0.4126) — an in-silico prediction, not a clinical call.

EPHB4 p.Gly893Arg

c.2677G>A · rs140332222 · VCV1597847

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4126 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.107%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4126	ambiguous
REVEL	0.273	benign-leaning
SaProt	LLR -7.60	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 3,002 bp · p 0.042 · regional, not allelic
Overall
CADD	27.7	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 0.107% African / African-American · 77/72,108 alleles

Filtering AF 0.0876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0805%

Overall 0.009% 137/1,522,118 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.107%	936
Remaining individualsnot grpmax-eligible	0.00855%	11,697
Finnishnot grpmax-eligible	0.00657%	15,226
East Asian	0.00456%	21,919
European (non-Finnish)	0.00432%	23,153

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.Gly893Arg
Coding: c.2677G>A
MANE Select: NM_004444
dbSNP: rs140332222
Type: single nucleotide variant
Location: chr7:100805502 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 893: a UniProt-annotated variant site (in cmavm2); the protein kinase 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.Gly893Val Uncertain significance ★ ⚠ 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-gly893arg (accessed [today's date]).

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