Is EPHX2 p.Pro259Ser (c.775C>T) pathogenic?

EPHX2 p.Pro259Ser (c.775C>T) is classified Uncertain significance in EPHX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: likely benign (0.2245); Ultra-rare (popmax 0.0147%, afr).

How common is EPHX2 p.Pro259Ser (c.775C>T) in the general population?

EPHX2 p.Pro259Ser (c.775C>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about EPHX2 p.Pro259Ser (c.775C>T)?

AlphaMissense predicts likely benign (score 0.2245) — an in-silico prediction, not a clinical call.

EPHX2 p.Pro259Ser

c.775C>T · rs143412145 · VCV3089719

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2245 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2245	likely benign
REVEL	0.391	indeterminate
SaProt	LLR -10.62	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 53 kb · p 0.64 · regional, not allelic
Overall
CADD	26.8	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 0.0147% African / African-American · 11/75,048 alleles

Filtering AF 0.00814% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00632%

Overall 0.00266% 43/1,614,088 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0208%	4,808
African / African-Americangrpmax	0.0147%	6,823
South Asian	0.0132%	7,590
East Asian	0.0111%	8,975
European (non-Finnish)	0.000169%	590,016

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro259Ser
Coding: c.775C>T
MANE Select: NM_001979
dbSNP: rs143412145
Type: single nucleotide variant
Location: chr8:27515757 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.54 · 141 PDB
Residue 259: the ab hydrolase-1 domain; the 'epoxide hydrolase' region; a β-strand

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

Similar variants

EPHX2 p.Arg403Trp Uncertain significance ★★ ⚠ same type
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-pro259ser (accessed [today's date]).

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