Is EPHB4 p.Arg659His (c.1976G>A) pathogenic?

EPHB4 p.Arg659His (c.1976G>A) is classified Uncertain significance in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-18). AlphaMissense: likely benign (0.2286); Very rare (popmax 0.00333%, amr); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Arg659His (c.1976G>A)?

EPHB4 p.Arg659His (c.1976G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Arg659His (c.1976G>A) in the general population?

EPHB4 p.Arg659His (c.1976G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about EPHB4 p.Arg659His (c.1976G>A)?

AlphaMissense predicts likely benign (score 0.2286) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg659His

c.1976G>A · rs776960865 · VCV1783717

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2286 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2286	likely benign
REVEL	0.709	pathogenic-leaning
SaProt	LLR -12.32	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 6,734 bp · p 5.4e-12 · regional, not allelic
Overall
CADD	32.0	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 0.00333% Admixed American · 2/60,008 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00124% 20/1,614,122 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,004
South Asian	0.00329%	30,363
African / African-American	0.00133%	74,944
European (non-Finnish)	0.00119%	84,289

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.Arg659His
Coding: c.1976G>A
MANE Select: NM_004444
dbSNP: rs776960865
Type: single nucleotide variant
Location: chr7:100812889 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 659: an α-helix; 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.Arg659= 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-arg659his (accessed [today's date]).

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