Is EPHX2 p.Lys89Arg (c.266A>G) pathogenic?

EPHX2 p.Lys89Arg (c.266A>G) is classified Benign in EPHX2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-28). AlphaMissense: likely benign (0.0746); Low-frequency (popmax 1.29%, afr); Associated with EPHX2-related disorder.

What condition is associated with EPHX2 p.Lys89Arg (c.266A>G)?

EPHX2 p.Lys89Arg (c.266A>G) is associated with EPHX2-related disorder (ClinVar).

How common is EPHX2 p.Lys89Arg (c.266A>G) in the general population?

EPHX2 p.Lys89Arg (c.266A>G) is low-frequency (popmax 1.29%, afr) (gnomAD).

What do computational predictors say about EPHX2 p.Lys89Arg (c.266A>G)?

AlphaMissense predicts likely benign (score 0.0746) — an in-silico prediction, not a clinical call.

EPHX2 p.Lys89Arg

c.266A>G · rs146918355 · VCV3056563

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0746 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.29%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EPHX2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0746	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -6.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.084	GERP -3.8
Regional constraint	o/e 1.02	unconstrained · MANE · 53 kb · p 0.64 · regional, not allelic
Overall
CADD	0.375	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 1.29% African / African-American · 966/75,016 alleles

Filtering AF 1.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.19%

Overall 0.067% 1,082/1,614,044 alleles · low-frequency exomes 495/1,461,804 · genomes 587/152,240 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.29%	78
Remaining individualsnot grpmax-eligible	0.0848%	1,179
Admixed American	0.0833%	1,200
Middle Eastern	0.0165%	6,062
South Asian	0.00329%	30,353
European (non-Finnish)	0.000763%	131,111

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.Lys89Arg
Coding: c.266A>G
MANE Select: NM_001979
dbSNP: rs146918355
Type: single nucleotide variant
Location: chr8:27503683 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.54 · 141 PDB
Residue 89: the 'phosphatase' region; an α-helix

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.Pro225Leu Likely benign same condition
EPHX2 p.Pro303= 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-lys89arg (accessed [today's date]).

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