Is EPHX2 p.Gly21= (c.63C>A) pathogenic?

EPHX2 p.Gly21= (c.63C>A) is classified Benign/Likely benign in EPHX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-01). Rare (popmax 0.768%, nfe).

How common is EPHX2 p.Gly21= (c.63C>A) in the general population?

EPHX2 p.Gly21= (c.63C>A) is rare (popmax 0.768%, nfe) (gnomAD).

EPHX2 p.Gly21=

c.63C>A · rs2234912 · VCV779344

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.768%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.022	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.2	GERP -0.16
Overall
CADD	8.915	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.768% European (non-Finnish) · 8,995/1,171,618 alleles

Filtering AF 0.754% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.749%

Overall 0.643% 10,143/1,578,248 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.953%	105
European (non-Finnish)grpmax	0.768%	130
Remaining individualsnot grpmax-eligible	0.572%	175
Admixed American	0.263%	380
African / African-American	0.137%	728
South Asian	0.094%	1,064
Middle Eastern	0.0701%	1,427
Ashkenazi Jewishnot grpmax-eligible	0.00347%	28,836

Finnish 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.Gly21=
Coding: c.63C>A
MANE Select: NM_001979
dbSNP: rs2234912
Type: single nucleotide variant
Location: chr8:27491271 (GRCh38)
Gene constraint: LOEUF 1.093 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.54 · 141 PDB
Residue 21: the 'phosphatase' region; a UniProt-annotated variant site (in); an α-helix

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

Similar variants

EPHX2 p.Gly21Ala Uncertain significance ★ ⚠ same residue
EPHX2 p.Gly21Asp Uncertain significance ★ ⚠ same residue
EPHX2 p.Arg403Trp Uncertain significance ★★ ⚠ same type
EPHX2 p.Arg52Gln 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

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-gly21 (accessed [today's date]).

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