Is EPHX2 p.Glu445Lys (c.1333G>A) pathogenic?

EPHX2 p.Glu445Lys (c.1333G>A) is classified Uncertain significance in EPHX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-07). AlphaMissense: likely benign (0.0896); Absent from gnomAD v4.1.

How common is EPHX2 p.Glu445Lys (c.1333G>A) in the general population?

EPHX2 p.Glu445Lys (c.1333G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EPHX2 p.Glu445Lys (c.1333G>A)?

AlphaMissense predicts likely benign (score 0.0896) — an in-silico prediction, not a clinical call.

EPHX2 p.Glu445Lys

c.1333G>A · VCV4664833

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0896 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0896	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -9.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.63 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.4	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 53 kb · p 0.64 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EPHX2
Protein: p.Glu445Lys
Coding: c.1333G>A
MANE Select: NM_001979
Type: single nucleotide variant
Location: chr8:27540610 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.54 · 141 PDB
Residue 445: 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-glu445lys (accessed [today's date]).

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