Is EPHB4 p.Gly182= (c.546T>C) pathogenic?

EPHB4 p.Gly182= (c.546T>C) is classified Benign/Likely benign in EPHB4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). Common (popmax 13.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Gly182= (c.546T>C)?

EPHB4 p.Gly182= (c.546T>C) is associated with Cardiovascular phenotype (ClinVar).

EPHB4 p.Gly182=

Q: How common is EPHB4 p.Gly182= (c.546T>C) in the general population?

EPHB4 p.Gly182= (c.546T>C) is common (popmax 13.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.546T>C · rs56173078 · VCV811644

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 13.7%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8	GERP -4.8
Overall
CADD	0.595	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.7% African / African-American · 10,271/75,012 alleles

Filtering AF 13.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 13.4%

Overall 7.93% 127,963/1,613,198 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	13.7%	7
South Asian	10.1%	10
Ashkenazi Jewishnot grpmax-eligible	9.73%	10
Finnishnot grpmax-eligible	8.78%	11
Remaining individualsnot grpmax-eligible	8.12%	12
European (non-Finnish)	7.61%	13
Amishnot grpmax-eligible	7.6%	13
Middle Eastern	6.93%	14
Admixed American	5.81%	17
East Asian	2.66%	38

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.Gly182=
Coding: c.546T>C
MANE Select: NM_004444
dbSNP: rs56173078
Type: single nucleotide variant
Location: chr7:100822533 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 182: a β-strand; a disulfide bond; a UniProt-annotated variant site (in cmavm2); 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 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-gly182 (accessed [today's date]).

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