Is EPHX2 p.Pro371Ser (c.1111C>T) pathogenic?

EPHX2 p.Pro371Ser (c.1111C>T) is classified Uncertain significance in EPHX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: likely benign (0.1776); Very rare (popmax 0.0022%, sas).

How common is EPHX2 p.Pro371Ser (c.1111C>T) in the general population?

EPHX2 p.Pro371Ser (c.1111C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about EPHX2 p.Pro371Ser (c.1111C>T)?

AlphaMissense predicts likely benign (score 0.1776) — an in-silico prediction, not a clinical call.

EPHX2 p.Pro371Ser

c.1111C>T · VCV4018860

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1776 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1776	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -10.81	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.4	GERP -3.1
Regional constraint	o/e 1.02	unconstrained · MANE · 53 kb · p 0.64 · regional, not allelic
Overall
CADD	0.218	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,078 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000205% 3/1,461,894 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,539
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.Pro371Ser
Coding: c.1111C>T
MANE Select: NM_001979
Type: single nucleotide variant
Location: chr8:27525414 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.54 · 141 PDB
Residue 371: 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

Similar variants

EPHX2 p.Arg403Trp Uncertain significance ★★ ⚠ same type
EPHX2 p.Arg52Gln Benign/Likely benign ★★ ⚠ same type
EPHX2 p.Gly21= Benign/Likely benign ★★ same type
EPHX2 p.Ala175Asp Uncertain significance ★ ⚠ same type
EPHX2 p.Ala18Val Uncertain significance ★ ⚠ same type
EPHX2 p.Ala260Ser Uncertain significance ★ ⚠ same type
EPHX2 p.Ala354Val Uncertain significance ★ ⚠ same type
EPHX2 p.Ala425Val Uncertain significance ★ ⚠ same type

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-pro371ser (accessed [today's date]).

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