Is EPHX2 p.Pro303= (c.909C>T) pathogenic?

EPHX2 p.Pro303= (c.909C>T) is classified Likely benign in EPHX2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-28). Ultra-rare (popmax 0.0133%, amr); Associated with EPHX2-related disorder.

What condition is associated with EPHX2 p.Pro303= (c.909C>T)?

EPHX2 p.Pro303= (c.909C>T) is associated with EPHX2-related disorder (ClinVar).

How common is EPHX2 p.Pro303= (c.909C>T) in the general population?

EPHX2 p.Pro303= (c.909C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

EPHX2 p.Pro303=

c.909C>T · rs757054443 · VCV3045333

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Conditions

EPHX2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.135	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.58 · evaluated, not missing
Constraint at this position
Conservation	phyloP -8.5	GERP -3.5
Overall
CADD	0.164	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/60,012 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00316% 51/1,613,838 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,501
South Asian	0.00659%	15,178
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.00271%	36,869
African / African-American	0.00133%	75,030

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.Pro303=
Coding: c.909C>T
MANE Select: NM_001979
dbSNP: rs757054443
Type: single nucleotide variant
Location: chr8:27516397 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.54 · 141 PDB
Residue 303: the ab hydrolase-1 domain; the 'epoxide hydrolase' region

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

Disease context

EPHX2-related disorder

Similar variants

EPHX2 p.Ala425= Benign same condition
EPHX2 p.Lys55Arg Benign same condition
EPHX2 p.Lys89Arg Benign same condition
EPHX2 p.Pro225Leu Likely benign same condition
EPHX2 p.Pro361Ser Benign ⚠ same condition
EPHX2 p.Ser270= Likely benign same condition
EPHX2 p.Ser412= Benign same condition
EPHX2 p.Arg403Trp 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-pro303 (accessed [today's date]).

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