Is EPHB4 p.Ser54= (c.162C>T) pathogenic?

EPHB4 p.Ser54= (c.162C>T) is classified Likely benign in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-28). Very rare (popmax 0.00493%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Ser54= (c.162C>T)?

EPHB4 p.Ser54= (c.162C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Ser54= (c.162C>T) in the general population?

EPHB4 p.Ser54= (c.162C>T) is very rare (popmax 0.00493%, nfe) (gnomAD).

EPHB4 p.Ser54=

c.162C>T · rs3735694 · VCV3224272

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00493%, nfe)

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 -3.1	GERP -4.7
Overall
CADD	4.393	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00493% European (non-Finnish) · 58/1,176,372 alleles

Filtering AF 0.00387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00354%

Overall 0.00374% 60/1,605,306 alleles · very rare exomes 55/1,452,940 · genomes 5/152,366 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00493%	20,282
East Asian	0.00225%	44,456
Remaining individualsnot grpmax-eligible	0.00161%	62,108

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.Ser54=
Coding: c.162C>T
MANE Select: NM_004444
dbSNP: rs3735694
Type: single nucleotide variant
Location: chr7:100823893 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 54: 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 p.Ser54Arg Uncertain significance ★ ⚠ same residue
EPHB4 p.Ser54Gly 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

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-ser54 (accessed [today's date]).

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