Is EPHB4 p.Arg56His (c.167G>A) pathogenic?

EPHB4 p.Arg56His (c.167G>A) is classified Uncertain significance in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-08). AlphaMissense: likely pathogenic (0.876); Very rare (popmax 0.00224%, eas); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Arg56His (c.167G>A)?

EPHB4 p.Arg56His (c.167G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Arg56His (c.167G>A) in the general population?

EPHB4 p.Arg56His (c.167G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about EPHB4 p.Arg56His (c.167G>A)?

AlphaMissense predicts likely pathogenic (score 0.876) — an in-silico prediction, not a clinical call.

EPHB4 p.Arg56His

c.167G>A · rs951495096 · VCV2562049

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.876 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.876	likely pathogenic
REVEL	0.407	indeterminate
SaProt	LLR -9.28	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
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	28.5	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 0.00224% East Asian · 1/44,576 alleles

Filtering AF 0.00088% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000719%

Overall 0.00124% 20/1,606,914 alleles · very rare exomes 18/1,454,688 · genomes 2/152,226 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,576
Remaining individualsnot grpmax-eligible	0.00161%	62,148
European (non-Finnish)	0.00144%	69,248
African / African-American	0.00134%	74,846

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.Arg56His
Coding: c.167G>A
MANE Select: NM_004444
dbSNP: rs951495096
Type: single nucleotide variant
Location: chr7:100823888 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 56: 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 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
EPHB4 p.Arg499Gln 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-arg56his (accessed [today's date]).

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