Is EPHB4 p.Leu717= (c.2151C>T) pathogenic?

EPHB4 p.Leu717= (c.2151C>T) is classified Likely benign in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-22). Ultra-rare (popmax 0.0373%, sas); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Leu717= (c.2151C>T)?

EPHB4 p.Leu717= (c.2151C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Leu717= (c.2151C>T) in the general population?

EPHB4 p.Leu717= (c.2151C>T) is ultra-rare (popmax 0.0373%, sas) (gnomAD).

EPHB4 p.Leu717=

c.2151C>T · rs112613465 · VCV1786760

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, sas)

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 0.28	GERP -3.7, phastCons 0.97
Overall
CADD	8.945	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0373% South Asian · 34/91,084 alleles

Filtering AF 0.0274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.024%

Overall 0.00514% 83/1,614,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0373%	2,679
Remaining individualsnot grpmax-eligible	0.0336%	2,976
African / African-American	0.024%	4,168
Admixed American	0.005%	20,001
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
European (non-Finnish)	0.000508%	196,669

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.Leu717=
Coding: c.2151C>T
MANE Select: NM_004444
dbSNP: rs112613465
Type: single nucleotide variant
Location: chr7:100807548 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 717: an α-helix; a UniProt-annotated variant site (in cmavm2); the protein kinase 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.Leu717Pro 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
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-leu717 (accessed [today's date]).

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