Is EPHX2 p.Ser412= (c.1236C>T) pathogenic?

EPHX2 p.Ser412= (c.1236C>T) is classified Benign in EPHX2 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2019-10-21). Common (popmax 10.7%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with EPHX2-related disorder.

What condition is associated with EPHX2 p.Ser412= (c.1236C>T)?

EPHX2 p.Ser412= (c.1236C>T) is associated with EPHX2-related disorder (ClinVar).

EPHX2 p.Ser412=

Q: How common is EPHX2 p.Ser412= (c.1236C>T) in the general population?

EPHX2 p.Ser412= (c.1236C>T) is common (popmax 10.7%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1236C>T · rs13439459 · VCV3060428

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 10.7%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

EPHX2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.5	GERP -2.1
Overall
CADD	1.241	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.7% European (non-Finnish) · 125,960/1,178,966 alleles

Filtering AF 10.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.6%

Overall 9.65% 155,352/1,610,520 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	10.7%	9
Middle Eastern	9.77%	10
Remaining individualsnot grpmax-eligible	9.28%	11
African / African-American	8.36%	12
Finnishnot grpmax-eligible	8.08%	12
Ashkenazi Jewishnot grpmax-eligible	7.97%	13
South Asian	6.45%	16
Admixed American	5.74%	17
Amishnot grpmax-eligible	4.96%	20
East Asian	0.0514%	1,946

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.Ser412=
Coding: c.1236C>T
MANE Select: NM_001979
dbSNP: rs13439459
Type: single nucleotide variant
Location: chr8:27536849 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.54 · 141 PDB
Residue 412: the ab hydrolase-1 domain; the 'epoxide hydrolase' 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.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.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-ser412 (accessed [today's date]).

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