Is EPHX3 p.Ser26Arg (c.78C>G) pathogenic?

EPHX3 p.Ser26Arg (c.78C>G) is classified Uncertain significance in EPHX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: likely pathogenic (0.785); Ultra-rare (popmax 0.0826%, afr).

How common is EPHX3 p.Ser26Arg (c.78C>G) in the general population?

EPHX3 p.Ser26Arg (c.78C>G) is ultra-rare (popmax 0.0826%, afr) (gnomAD).

What do computational predictors say about EPHX3 p.Ser26Arg (c.78C>G)?

AlphaMissense predicts likely pathogenic (score 0.785) — an in-silico prediction, not a clinical call.

EPHX3 p.Ser26Arg

c.78C>G · rs534088623 · VCV2380357

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.785 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0826%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.785	likely pathogenic
REVEL	0.093	moderately benign-leaning
SaProt	LLR -10.30	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 1.9	GERP -0.055, phastCons 0.97
Regional constraint	o/e 0.93	unconstrained · MANE · 4,771 bp · p 0.14 · regional, not allelic
Overall
CADD	15.81	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 0.0826% African / African-American · 60/72,648 alleles

Filtering AF 0.0659% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0598%

Overall 0.00441% 68/1,540,260 alleles · ultra-rare exomes 28/1,387,996 · genomes 40/152,264 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0826%	1,211
Remaining individualsnot grpmax-eligible	0.00832%	12,018
Admixed American	0.00583%	17,163

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.Ser26Arg
Coding: c.78C>G
MANE Select: NM_024794
dbSNP: rs534088623
Type: single nucleotide variant
Location: chr19:15232134 (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-ser26arg (accessed [today's date]).

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