Is EPM2A p.Ala227= (c.681C>T) pathogenic?

EPM2A p.Ala227= (c.681C>T) is classified Likely benign in EPM2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-28). Rare (popmax 0.208%, afr); Associated with progressive myoclonus epilepsy.

What condition is associated with EPM2A p.Ala227= (c.681C>T)?

EPM2A p.Ala227= (c.681C>T) is associated with progressive myoclonus epilepsy (ClinVar).

How common is EPM2A p.Ala227= (c.681C>T) in the general population?

EPM2A p.Ala227= (c.681C>T) is rare (popmax 0.208%, afr) (gnomAD).

EPM2A p.Ala227=

c.681C>T · rs61758156 · VCV416699

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.208%, afr)

Conditions

progressive myoclonus epilepsy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.019	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -1.8, phastCons 1
Overall
CADD	10.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.208% African / African-American · 156/75,022 alleles

Filtering AF 0.181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.171%

Overall 0.0105% 169/1,614,070 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.208%	481
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0096%	10,416
Admixed American	0.00666%	15,006
European (non-Finnish)	8.47e-05%	1,179,967

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: EPM2A
Protein: p.Ala227=
Coding: c.681C>T
MANE Select: NM_005670
dbSNP: rs61758156
Type: single nucleotide variant
Location: chr6:145635282 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 34.25 · 2 PDB
Residue 227: a β-strand; the tyrosine-protein phosphatase domain

Full EPM2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

progressive myoclonus epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EPM2A p.Ala227Val Conflicting classifications of pathogenicity ★ same residue
EPM2A c.301+1G>T Pathogenic ★★ same condition
EPM2A c.302-1G>C Pathogenic/Likely pathogenic ★★ same condition
EPM2A c.302-2A>G Pathogenic ★★ same condition
EPM2A p.Arg108Cys Pathogenic/Likely pathogenic ★★ same condition
EPM2A p.Arg171His Pathogenic/Likely pathogenic ★★ same condition
EPM2A p.Arg241Ter Pathogenic/Likely pathogenic ★★ same condition
EPM2A p.Gly279Cys Pathogenic/Likely pathogenic ★★ same condition

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/epm2a-p-ala227 (accessed [today's date]).

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