Is EPHX3 p.Leu33Pro (c.98T>C) pathogenic?

EPHX3 p.Leu33Pro (c.98T>C) is classified Uncertain significance in EPHX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-30). AlphaMissense: ambiguous (0.3785); Ultra-rare (popmax 0.0563%, amr).

How common is EPHX3 p.Leu33Pro (c.98T>C) in the general population?

EPHX3 p.Leu33Pro (c.98T>C) is ultra-rare (popmax 0.0563%, amr) (gnomAD).

What do computational predictors say about EPHX3 p.Leu33Pro (c.98T>C)?

AlphaMissense predicts ambiguous (score 0.3785) — an in-silico prediction, not a clinical call.

EPHX3 p.Leu33Pro

c.98T>C · rs1247025754 · VCV3089728

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3785 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0563%, amr)

Computational evidence

Protein change
AlphaMissense	0.3785	ambiguous
REVEL	0.358	indeterminate
SaProt	LLR -14.89	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.1, phastCons 0.43
Regional constraint	o/e 0.93	unconstrained · MANE · 4,771 bp · p 0.14 · regional, not allelic
Overall
CADD	20.4	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 0.0563% Admixed American · 26/46,186 alleles

Filtering AF 0.0394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0338%

Overall 0.00215% 32/1,487,854 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0563%	1,776
African / African-American	0.00314%	31,845
Remaining individualsnot grpmax-eligible	0.00172%	58,142
European (non-Finnish)	0.000267%	374,500

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.Leu33Pro
Coding: c.98T>C
MANE Select: NM_024794
dbSNP: rs1247025754
Type: single nucleotide variant
Location: chr19:15232114 (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.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
EPHX3 p.Arg118Gln 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-leu33pro (accessed [today's date]).

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