Is EPHX2 p.Phe381Leu (c.1143T>A) pathogenic?

EPHX2 p.Phe381Leu (c.1143T>A) is classified Uncertain significance in EPHX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely pathogenic (0.906); Very rare (popmax 8.47e-05%, nfe).

How common is EPHX2 p.Phe381Leu (c.1143T>A) in the general population?

EPHX2 p.Phe381Leu (c.1143T>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about EPHX2 p.Phe381Leu (c.1143T>A)?

AlphaMissense predicts likely pathogenic (score 0.906) — an in-silico prediction, not a clinical call.

EPHX2 p.Phe381Leu

c.1143T>A · VCV3509465

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.906 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.906	likely pathogenic · top 5% in EPHX2
REVEL	0.212	benign-leaning
SaProt	LLR -8.25	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -3
Regional constraint	o/e 1.02	unconstrained · MANE · 53 kb · p 0.64 · regional, not allelic
Overall
CADD	9.847	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 8.47e-05% European (non-Finnish) · 1/1,180,008 alleles

Overall 6.84e-05% 1/1,461,866 alleles · very rare

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.Phe381Leu
Coding: c.1143T>A
MANE Select: NM_001979
Type: single nucleotide variant
Location: chr8:27525446 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.54 · 141 PDB
Residue 381: 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-phe381leu (accessed [today's date]).

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