Is EPHX2 p.Arg403Trp (c.1207C>T) pathogenic?

EPHX2 p.Arg403Trp (c.1207C>T) is classified Uncertain significance in EPHX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-13). AlphaMissense: likely benign (0.2096); Ultra-rare (popmax 0.0518%, amr).

How common is EPHX2 p.Arg403Trp (c.1207C>T) in the general population?

EPHX2 p.Arg403Trp (c.1207C>T) is ultra-rare (popmax 0.0518%, amr) (gnomAD).

What do computational predictors say about EPHX2 p.Arg403Trp (c.1207C>T)?

AlphaMissense predicts likely benign (score 0.2096) — an in-silico prediction, not a clinical call.

EPHX2 p.Arg403Trp

c.1207C>T · rs772415390 · VCV2400249

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2096 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0518%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2096	likely benign
REVEL	0.565	indeterminate
SaProt	LLR -4.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 1.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 53 kb · p 0.64 · regional, not allelic
Overall
CADD	28.5	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 0.0518% Admixed American · 31/59,822 alleles

Filtering AF 0.0375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0326%

Overall 0.00285% 46/1,612,610 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0518%	1,930
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Remaining individualsnot grpmax-eligible	0.0016%	62,462
African / African-American	0.00134%	74,358
South Asian	0.0011%	91,004
European (non-Finnish)	0.000932%	107,259

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.Arg403Trp
Coding: c.1207C>T
MANE Select: NM_001979
dbSNP: rs772415390
Type: single nucleotide variant
Location: chr8:27536820 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.54 · 141 PDB
Residue 403: the ab hydrolase-1 domain; the 'epoxide hydrolase' region; a UniProt-annotated variant site (sequence variant); an α-helix

Full EPHX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPHX2 p.Arg403Gly Uncertain significance ★ ⚠ same residue
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-arg403trp (accessed [today's date]).

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