Is EPHB4 p.Ser325= (c.975G>A) pathogenic?

EPHB4 p.Ser325= (c.975G>A) is classified Likely benign in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-30). Ultra-rare (popmax 0.055%, mid); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Ser325= (c.975G>A)?

EPHB4 p.Ser325= (c.975G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Ser325= (c.975G>A) in the general population?

EPHB4 p.Ser325= (c.975G>A) is ultra-rare (popmax 0.055%, mid) (gnomAD).

EPHB4 p.Ser325=

c.975G>A · rs540693969 · VCV1768103

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.055%, mid)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -15	GERP -5
Overall
CADD	0.246	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.055% Middle Eastern · 3/5,456 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00797%

Overall 0.00162% 25/1,544,568 alleles · ultra-rare exomes 18/1,392,276 · genomes 7/152,292 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.055%	1,819
African / African-American	0.0123%	8,118
Remaining individualsnot grpmax-eligible	0.00502%	19,913
Admixed American	0.00393%	25,440
South Asian	0.00238%	42,037
European (non-Finnish)	0.000525%	190,452

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.Ser325=
Coding: c.975G>A
MANE Select: NM_004444
dbSNP: rs540693969
Type: single nucleotide variant
Location: chr7:100819879 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 325: a UniProt-annotated variant site (in cmavm2); the fibronectin type-iii 1 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-ser325 (accessed [today's date]).

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