Is EPHB4 p.Leu341= (c.1021C>T) pathogenic?

EPHB4 p.Leu341= (c.1021C>T) is classified Likely benign in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-15). Ultra-rare (popmax 0.0136%, afr); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Leu341= (c.1021C>T)?

EPHB4 p.Leu341= (c.1021C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Leu341= (c.1021C>T) in the general population?

EPHB4 p.Leu341= (c.1021C>T) is ultra-rare (popmax 0.0136%, afr) (gnomAD).

EPHB4 p.Leu341=

c.1021C>T · rs749864365 · VCV1760862

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, afr)

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 4.4	GERP 1.4, phastCons 1
Overall
CADD	11.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0136% African / African-American · 10/73,322 alleles

Filtering AF 0.00738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0058%

Overall 0.00656% 102/1,555,858 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0136%	7,332
European (non-Finnish)	0.00756%	13,219
Remaining individualsnot grpmax-eligible	0.00664%	15,070
Finnishnot grpmax-eligible	0.0017%	58,838

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.Leu341=
Coding: c.1021C>T
MANE Select: NM_004444
dbSNP: rs749864365
Type: single nucleotide variant
Location: chr7:100819833 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 341: 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-leu341 (accessed [today's date]).

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