Is EPHB4 p.Pro168Leu (c.503C>T) pathogenic?

EPHB4 p.Pro168Leu (c.503C>T) is classified Likely benign in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-26). AlphaMissense: likely benign (0.2496); Very rare (popmax 0.00501%, amr); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Pro168Leu (c.503C>T)?

EPHB4 p.Pro168Leu (c.503C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Pro168Leu (c.503C>T) in the general population?

EPHB4 p.Pro168Leu (c.503C>T) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about EPHB4 p.Pro168Leu (c.503C>T)?

AlphaMissense predicts likely benign (score 0.2496) — an in-silico prediction, not a clinical call.

EPHB4 p.Pro168Leu

c.503C>T · rs777267049 · VCV2407744

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2496 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2496	likely benign
REVEL	0.529	indeterminate
SaProt	LLR -11.44	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 14 kb · p 0.00047 · regional, not allelic
Overall
CADD	29.4	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 0.00501% Admixed American · 3/59,908 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000682% 11/1,612,484 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,969
South Asian	0.0033%	30,339
European (non-Finnish)	0.000424%	235,918

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.Pro168Leu
Coding: c.503C>T
MANE Select: NM_004444
dbSNP: rs777267049
Type: single nucleotide variant
Location: chr7:100822576 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 168: 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 p.Pro168= 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-pro168leu (accessed [today's date]).

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