Is EPHX2 p.Pro361Ser (c.1081C>T) pathogenic?

EPHX2 p.Pro361Ser (c.1081C>T) is classified Benign in EPHX2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-10). AlphaMissense: likely pathogenic (0.7179); Low-frequency (popmax 1.28%, sas); Associated with EPHX2-related disorder.

What condition is associated with EPHX2 p.Pro361Ser (c.1081C>T)?

EPHX2 p.Pro361Ser (c.1081C>T) is associated with EPHX2-related disorder (ClinVar).

How common is EPHX2 p.Pro361Ser (c.1081C>T) in the general population?

EPHX2 p.Pro361Ser (c.1081C>T) is low-frequency (popmax 1.28%, sas) (gnomAD).

What do computational predictors say about EPHX2 p.Pro361Ser (c.1081C>T)?

AlphaMissense predicts likely pathogenic (score 0.7179) — an in-silico prediction, not a clinical call.

EPHX2 p.Pro361Ser

c.1081C>T · rs201276018 · VCV3058383

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7179 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.28%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

EPHX2-related disorder

Computational evidence

Protein change
AlphaMissense	0.7179	likely pathogenic
REVEL	0.459	indeterminate
SaProt	LLR -9.86	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 53 kb · p 0.64 · regional, not allelic
Overall
CADD	26.5	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 1.28% South Asian · 1,169/91,076 alleles

Filtering AF 1.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.2%

Overall 0.0776% 1,253/1,614,118 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.28%	78
Remaining individualsnot grpmax-eligible	0.0992%	1,008
Middle Eastern	0.066%	1,516
Admixed American	0.00833%	12,004
East Asian	0.00223%	44,878
African / African-American	0.00133%	75,002
European (non-Finnish)	0.000932%	107,274

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.Pro361Ser
Coding: c.1081C>T
MANE Select: NM_001979
dbSNP: rs201276018
Type: single nucleotide variant
Location: chr8:27525384 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.54 · 141 PDB
Residue 361: 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.Ala425= Benign same condition
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.Ser270= Likely benign same condition
EPHX2 p.Ser412= Benign same condition
EPHX2 p.Arg403Trp 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-pro361ser (accessed [today's date]).

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