Is EPM2A p.Trp165Ter (c.495G>A) pathogenic?

EPM2A p.Trp165Ter (c.495G>A) is classified Pathogenic/Likely pathogenic in EPM2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-22). Very rare (popmax 0.00339%, nfe); Associated with Lafora disease.

What condition is associated with EPM2A p.Trp165Ter (c.495G>A)?

EPM2A p.Trp165Ter (c.495G>A) is associated with Lafora disease, progressive myoclonus epilepsy (ClinVar).

How common is EPM2A p.Trp165Ter (c.495G>A) in the general population?

EPM2A p.Trp165Ter (c.495G>A) is very rare (popmax 0.00339%, nfe) (gnomAD).

How is Lafora disease inherited?

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

EPM2A p.Trp165Ter

c.495G>A · rs781291421 · VCV381553

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Conditions

Lafora disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 4
REVEL	0.203	benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.34 · evaluated, not missing
Pangolin	Δ0.20	loss · gain 0.10 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Overall
CADD	43.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00339% European (non-Finnish) · 40/1,179,864 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00254% 41/1,613,866 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,497
African / African-American	0.00133%	74,914

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.Trp165Ter
Coding: c.495G>A
MANE Select: NM_005670
dbSNP: rs781291421
Type: single nucleotide variant
Location: chr6:145635468 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 34.25 · 2 PDB
Residue 165: the 'disordered' region; the tyrosine-protein phosphatase domain; a β-strand

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

Also linked: progressive myoclonus epilepsy

For Lafora disease (Orphanet):

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

Similar variants

EPM2A p.Trp165Cys 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-trp165ter (accessed [today's date]).

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