Is EPHX2 p.Ala425= (c.1275G>A) pathogenic?

EPHX2 p.Ala425= (c.1275G>A) is classified Benign in EPHX2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-21). Common (popmax 20.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with EPHX2-related disorder.

What condition is associated with EPHX2 p.Ala425= (c.1275G>A)?

EPHX2 p.Ala425= (c.1275G>A) is associated with EPHX2-related disorder (ClinVar).

EPHX2 p.Ala425=

Q: How common is EPHX2 p.Ala425= (c.1275G>A) in the general population?

EPHX2 p.Ala425= (c.1275G>A) is common (popmax 20.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1275G>A · rs4149253 · VCV3055553

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 20.8%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

EPHX2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.30	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 1.1	GERP 0.59, phastCons 0.7
Overall
CADD	13.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 20.8% East Asian · 9,336/44,852 alleles

Filtering AF 20.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 20.3%

Overall 6.41% 103,434/1,613,174 alleles · common exomes 91,572/1,460,926 · genomes 11,862/152,248 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	20.8%	5
Ashkenazi Jewishnot grpmax-eligible	11.8%	8
African / African-American	10.8%	9
Middle Eastern	10.1%	10
South Asian	10.1%	10
Remaining individualsnot grpmax-eligible	7.33%	14
Admixed American	6.84%	15
Amishnot grpmax-eligible	6.81%	15
Finnishnot grpmax-eligible	5.24%	19
European (non-Finnish)	5.14%	19

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: EPHX2
Protein: p.Ala425=
Coding: c.1275G>A
MANE Select: NM_001979
dbSNP: rs4149253
Type: single nucleotide variant
Location: chr8:27538691 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.54 · 141 PDB
Residue 425: the ab hydrolase-1 domain; the 'epoxide hydrolase' region; an α-helix

Full EPHX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

EPHX2-related disorder

Similar variants

EPHX2 p.Ala425Val Uncertain significance ★ ⚠ same residue
EPHX2 p.Lys55Arg Benign same condition
EPHX2 p.Lys89Arg Benign same condition
EPHX2 p.Pro225Leu Likely benign same condition
EPHX2 p.Pro303= Likely benign same condition
EPHX2 p.Pro361Ser Benign ⚠ same condition
EPHX2 p.Ser270= Likely benign same condition
EPHX2 p.Ser412= Benign 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/ephx2-p-ala425 (accessed [today's date]).

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