Is EPHB4 p.Thr127= (c.381G>A) pathogenic?

EPHB4 p.Thr127= (c.381G>A) is classified Likely benign in EPHB4 (ClinVar, Single submitter, 2 submitters; last evaluated 2019-08-19). Rare (popmax 0.158%, sas); Associated with Cardiovascular phenotype.

What condition is associated with EPHB4 p.Thr127= (c.381G>A)?

EPHB4 p.Thr127= (c.381G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is EPHB4 p.Thr127= (c.381G>A) in the general population?

EPHB4 p.Thr127= (c.381G>A) is rare (popmax 0.158%, sas) (gnomAD).

EPHB4 p.Thr127=

c.381G>A · rs749343839 · VCV1735251

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.158%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -12	GERP -4.4
Overall
CADD	0.663	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.158% South Asian · 144/91,082 alleles

Filtering AF 0.137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.129%

Overall 0.0108% 175/1,613,126 alleles · rare exomes 164/1,460,902 · genomes 11/152,224 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.158%	633
Admixed American	0.015%	6,668
Remaining individualsnot grpmax-eligible	0.0112%	8,925
African / African-American	0.00267%	37,465
East Asian	0.00223%	44,880
European (non-Finnish)	0.00102%	98,323

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.Thr127=
Coding: c.381G>A
MANE Select: NM_004444
dbSNP: rs749343839
Type: single nucleotide variant
Location: chr7:100823674 (GRCh38)
Gene constraint: LOEUF 0.645 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.46 · 23 PDB
Residue 127: 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.Thr127Met Conflicting classifications of pathogenicity ★ ⚠ 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-thr127 (accessed [today's date]).

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