Is EPHX2 p.Thr77Pro (c.229A>C) pathogenic?

EPHX2 p.Thr77Pro (c.229A>C) is classified Uncertain significance in EPHX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-23). AlphaMissense: likely benign (0.1055); Very rare (popmax 0.00017%, nfe).

How common is EPHX2 p.Thr77Pro (c.229A>C) in the general population?

EPHX2 p.Thr77Pro (c.229A>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about EPHX2 p.Thr77Pro (c.229A>C)?

AlphaMissense predicts likely benign (score 0.1055) — an in-silico prediction, not a clinical call.

EPHX2 p.Thr77Pro

c.229A>C · VCV3845506

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1055 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1055	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -11.40	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 3.9	GERP -1.3, phastCons 0.97
Regional constraint	o/e 1.02	unconstrained · MANE · 53 kb · p 0.64 · regional, not allelic
Overall
CADD	10.17	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 0.00017% European (non-Finnish) · 2/1,179,906 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,478 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.Thr77Pro
Coding: c.229A>C
MANE Select: NM_001979
Type: single nucleotide variant
Location: chr8:27503646 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.54 · 141 PDB
Residue 77: the 'phosphatase' region; a turn

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-thr77pro (accessed [today's date]).

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