Is EPM2A p.Asp306Val (c.917A>T) pathogenic?

EPM2A p.Asp306Val (c.917A>T) is classified Uncertain significance in EPM2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-03). Very rare (popmax 8.47e-05%, nfe); Associated with Lafora disease.

What condition is associated with EPM2A p.Asp306Val (c.917A>T)?

EPM2A p.Asp306Val (c.917A>T) is associated with Lafora disease (ClinVar).

How common is EPM2A p.Asp306Val (c.917A>T) in the general population?

EPM2A p.Asp306Val (c.917A>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Lafora disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

EPM2A p.Asp306Val

c.917A>T · rs1064797330 · VCV425396

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Lafora disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.893	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 108 kb · p 0.41 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,042 alleles

Overall 6.84e-05% 1/1,461,892 alleles · very rare

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.Asp306Val
Coding: c.917A>T
MANE Select: NM_005670
dbSNP: rs1064797330
Type: single nucleotide variant
Location: chr6:145627495 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 34.25 · 2 PDB
Residue 306: the tyrosine-protein phosphatase domain

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

Disease context

Lafora disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lafora disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood
Prevalence: 1-9 / 1 000 000 (France)

Similar variants

EPM2A p.Asp306= Likely benign ★★ 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-asp306val (accessed [today's date]).

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