Is EPHX4 p.Ala32Pro (c.94G>C) pathogenic?

EPHX4 p.Ala32Pro (c.94G>C) is classified Uncertain significance in EPHX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-21). AlphaMissense: likely pathogenic (0.7545); Very rare (popmax 0.00501%, amr).

How common is EPHX4 p.Ala32Pro (c.94G>C) in the general population?

EPHX4 p.Ala32Pro (c.94G>C) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about EPHX4 p.Ala32Pro (c.94G>C)?

AlphaMissense predicts likely pathogenic (score 0.7545) — an in-silico prediction, not a clinical call.

EPHX4 p.Ala32Pro

c.94G>C · VCV4018875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7545 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7545	likely pathogenic
REVEL	0.169	moderately benign-leaning
SaProt	LLR -11.77	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 0.15, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 33 kb · p 0.0019 · regional, not allelic
Overall
CADD	21.8	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 0.00501% Admixed American · 3/59,888 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000669%

Overall 0.000205% 3/1,460,040 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: EPHX4
Protein: p.Ala32Pro
Coding: c.94G>C
MANE Select: NM_173567
Type: single nucleotide variant
Location: chr1:92030173 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.95

Full EPHX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHX4 p.Ala32Val Uncertain significance ★ ⚠ same residue
EPHX4 p.Ala135Val Uncertain significance ★ ⚠ same type
EPHX4 p.Ala209Thr Uncertain significance ★ ⚠ same type
EPHX4 p.Ala308Thr Uncertain significance ★ ⚠ same type
EPHX4 p.Arg10His Uncertain significance ★ ⚠ same type
EPHX4 p.Arg114Gly Uncertain significance ★ ⚠ same type
EPHX4 p.Arg121Gln Uncertain significance ★ same type
EPHX4 p.Asn233Ser 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/ephx4-p-ala32pro (accessed [today's date]).

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