Is EPHB4 p.Leu347= (c.1039C>T) pathogenic?

EPHB4 p.Leu347= (c.1039C>T) is classified Likely benign in EPHB4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-21). Very rare (popmax 0.00295%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Leu347= (c.1039C>T)?

EPHB4 p.Leu347= (c.1039C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Leu347= (c.1039C>T) in the general population?

EPHB4 p.Leu347= (c.1039C>T) is very rare (popmax 0.00295%, nfe) (gnomAD).

EPHB4 p.Leu347=

c.1039C>T · rs758060600 · VCV1773495

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00295%, nfe)

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 6.5	GERP 2.5, phastCons 1
Overall
CADD	10.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00295% European (non-Finnish) · 34/1,153,038 alleles

Filtering AF 0.00212% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00187%

Overall 0.00224% 35/1,560,974 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00295%	33,913
Remaining individualsnot grpmax-eligible	0.00165%	60,504

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.Leu347=
Coding: c.1039C>T
MANE Select: NM_004444
dbSNP: rs758060600
Type: single nucleotide variant
Location: chr7:100819815 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 347: 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 p.Leu347fs Pathogenic ★★ 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-leu347 (accessed [today's date]).

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