Is EPHX3 p.Val47Ala (c.140T>C) pathogenic?

EPHX3 p.Val47Ala (c.140T>C) is classified Uncertain significance in EPHX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely benign (0.3068); Very rare (popmax 8.58e-05%, nfe).

How common is EPHX3 p.Val47Ala (c.140T>C) in the general population?

EPHX3 p.Val47Ala (c.140T>C) is very rare (popmax 8.58e-05%, nfe) (gnomAD).

What do computational predictors say about EPHX3 p.Val47Ala (c.140T>C)?

AlphaMissense predicts likely benign (score 0.3068) — an in-silico prediction, not a clinical call.

EPHX3 p.Val47Ala

c.140T>C · VCV3845513

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3068 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.58e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3068	likely benign
REVEL	0.222	benign-leaning
SaProt	LLR -6.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 0.97, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,771 bp · p 0.14 · regional, not allelic
Overall
CADD	23.8	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

Grpmax group 8.58e-05% European (non-Finnish) · 1/1,165,468 alleles

Overall 6.36e-05% 1/1,571,446 alleles · very rare exomes 1/1,419,354 · genomes 0/152,092 · joint denominator

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: EPHX3
Protein: p.Val47Ala
Coding: c.140T>C
MANE Select: NM_024794
Type: single nucleotide variant
Location: chr19:15232072 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.38

Full EPHX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHX3 p.Val47Met Uncertain significance ★ ⚠ same residue
EPHX3 p.Ala176Asp Uncertain significance ★ ⚠ same type
EPHX3 p.Ala176Thr Uncertain significance ★ ⚠ same type
EPHX3 p.Ala22Ser Uncertain significance ★ ⚠ same type
EPHX3 p.Ala65Ser Uncertain significance ★ ⚠ same type
EPHX3 p.Ala65Thr Uncertain significance ★ ⚠ same type
EPHX3 p.Arg114Cys Uncertain significance ★ ⚠ same type
EPHX3 p.Arg114His 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/ephx3-p-val47ala (accessed [today's date]).

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