EPM2A

Chr 6AR

EPM2A glucan phosphatase, laforin

Also known as: EPM2, MELF, MELF2

NCBI Gene: 7957 ENSG00000112425 UniProt: B3EWF7 OMIM: 607566

The protein is a dual-specificity phosphatase that prevents glycogen hyperphosphorylation by acting on complex carbohydrates, thereby avoiding formation of insoluble glycogen aggregates. Mutations cause Lafora disease (myoclonic epilepsy of Lafora type 1), a rare neurodegenerative disorder with adult onset characterized by myoclonus epilepsy and accumulation of insoluble glycogen-derived particles called Lafora bodies. Inheritance is autosomal recessive.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM

This gene encodes a dual-specificity phosphatase and may be involved in the regulation of glycogen metabolism. The protein acts on complex carbohydrates to prevent glycogen hyperphosphorylation, thus avoiding the formation of insoluble aggregates. Loss-of-function mutations in this gene have been associated with Lafora disease, a rare, adult-onset recessive neurodegenerative disease, which results in myoclonus epilepsy and usually results in death several years after the onset of symptoms. The disease is characterized by the accumulation of insoluble particles called Lafora bodies, which are derived from glycogen. [provided by RefSeq, Jan 2018]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Myoclonic epilepsy of Lafora 1MIM #254780

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Lafora disease · AR · ClinGen 2020

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.34

LOEUF

GOF

Mechanism· predicted

📖

GeneReview available — EPM2A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.34LOEUF

pLI 0.000

Z-score 0.73

OE 0.77 (0.46–1.34)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.26Z-score

OE missense 1.06 (0.93–1.20)

165 obs / 155.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.77 (0.46–1.34)

0≤0.351.4

Missense OE?1.06 (0.93–1.20)

0≤0.61.4

Synonymous OE?1.27

0≤1.21.6

LoF obs/exp: 9 / 11.7Missense obs/exp: 165 / 155.9Syn Z: -1.64

Background carrier burden — how many people carry a rare variant somewhere in EPM2A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 71

590 rare PASS variants

Rare truncating (LoF)

1 in 980

92 rare PASS variants

Rare synonymous (reference)

1 in 340

194 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for EPM2A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 79	1 in 1,100
South Asian	~43k	1 in 83	1 in 640
Remaining (unassigned)	~30k	1 in 62	1 in 1,600
European (Finnish)	~27k	1 in 200	1 in 2,800
Admixed American	~22k	1 in 56	1 in 1,300
African / African American	~21k	1 in 84	1 in 1,700
East Asian	~20k	1 in 170	1 in 1,100
Ashkenazi Jewish	~13k	1 in 210	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 100	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 3 of 4 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 4.? see exons ↓