Is EPM2A p.Phe321Cys (c.962T>G) pathogenic?

EPM2A p.Phe321Cys (c.962T>G) is classified Uncertain significance in EPM2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-03). Ultra-rare (popmax 0.0253%, sas); Associated with progressive myoclonus epilepsy.

What condition is associated with EPM2A p.Phe321Cys (c.962T>G)?

EPM2A p.Phe321Cys (c.962T>G) is associated with progressive myoclonus epilepsy, Lafora disease (ClinVar).

How common is EPM2A p.Phe321Cys (c.962T>G) in the general population?

EPM2A p.Phe321Cys (c.962T>G) is ultra-rare (popmax 0.0253%, sas) (gnomAD).

EPM2A p.Phe321Cys

c.962T>G · rs772620616 · VCV1449816

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, sas)

Conditions

progressive myoclonus epilepsy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.808	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 108 kb · p 0.41 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0253% South Asian · 23/91,076 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00142% 23/1,614,188 alleles · ultra-rare exomes 23/1,461,894 · genomes 0/152,294 · joint denominator

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.Phe321Cys
Coding: c.962T>G
MANE Select: NM_005670
dbSNP: rs772620616
Type: single nucleotide variant
Location: chr6:145627450 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 34.25 · 2 PDB
Residue 321: the 'disordered' region; an α-helix; 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

Also linked: Lafora disease

Similar variants

EPM2A p.Phe321Ser Uncertain significance ★ 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.Gln293Leu 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-phe321cys (accessed [today's date]).

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