Is EPHB4 p.Leu20= (c.58C>T) pathogenic?

EPHB4 p.Leu20= (c.58C>T) is classified Likely benign in EPHB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-23). Rare (popmax 0.114%, sas); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Leu20= (c.58C>T)?

EPHB4 p.Leu20= (c.58C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Leu20= (c.58C>T) in the general population?

EPHB4 p.Leu20= (c.58C>T) is rare (popmax 0.114%, sas) (gnomAD).

EPHB4 p.Leu20=

c.58C>T · rs372997648 · VCV1750383

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.114%, 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 4.6	GERP -1.7, phastCons 1
Overall
CADD	9.631	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.114% South Asian · 104/91,090 alleles

Filtering AF 0.0964% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0897%

Overall 0.00725% 117/1,614,116 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.114%	876
Remaining individualsnot grpmax-eligible	0.016%	6,251
Admixed American	0.00167%	60,006
African / African-American	0.00133%	75,038
European (non-Finnish)	8.47e-05%	1,179,994

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.Leu20=
Coding: c.58C>T
MANE Select: NM_004444
dbSNP: rs372997648
Type: single nucleotide variant
Location: chr7:100824268 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 20: 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 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-leu20 (accessed [today's date]).

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