Is EPHX2 p.Lys55Arg (c.164A>G) pathogenic?

EPHX2 p.Lys55Arg (c.164A>G) is classified Benign in EPHX2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-21). AlphaMissense: likely benign (0.0642); Common (popmax 22.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with EPHX2-related disorder.

What condition is associated with EPHX2 p.Lys55Arg (c.164A>G)?

EPHX2 p.Lys55Arg (c.164A>G) is associated with EPHX2-related disorder (ClinVar).

What do computational predictors say about EPHX2 p.Lys55Arg (c.164A>G)?

AlphaMissense predicts likely benign (score 0.0642) — an in-silico prediction, not a clinical call.

EPHX2 p.Lys55Arg

Q: How common is EPHX2 p.Lys55Arg (c.164A>G) in the general population?

EPHX2 p.Lys55Arg (c.164A>G) is common (popmax 22.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.164A>G · rs41507953 · VCV3059509

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0642 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 22.3%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

EPHX2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0642	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -3.87	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 -2.5	GERP -3.5
Regional constraint	o/e 1.02	unconstrained · MANE · 53 kb · p 0.64 · regional, not allelic
Overall
CADD	0.035	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 22.3% African / African-American · 16,657/74,788 alleles

Filtering AF 22% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.9%

Overall 10.5% 169,177/1,612,256 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	22.3%	4
European (non-Finnish)	10.9%	9
Middle Eastern	10.6%	9
Remaining individualsnot grpmax-eligible	10.4%	10
Finnishnot grpmax-eligible	8.14%	12
Ashkenazi Jewishnot grpmax-eligible	8.13%	12
South Asian	6.5%	15
Admixed American	6.46%	15
Amishnot grpmax-eligible	4.93%	20
East Asian	0.0334%	2,991

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.Lys55Arg
Coding: c.164A>G
MANE Select: NM_001979
dbSNP: rs41507953
Type: single nucleotide variant
Location: chr8:27500988 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.54 · 141 PDB
Residue 55: a modified residue (n6-succinyllysine); the 'phosphatase' region; a UniProt-annotated variant site (decreased phosphatase activity; no effect on epoxyde hydrolase activity)

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.Lys89Arg 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-lys55arg (accessed [today's date]).

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