# NM_005670.4(EPM2A):c.252C>T (p.Phe84=)

https://sugi.bio/variant/epm2a-p-phe84

## Summary

**EPM2A p.Phe84= (c.252C>T)** is classified **Likely benign** in EPM2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-19). Very rare (popmax 0.000701%, nfe); Associated with progressive myoclonus epilepsy.

**At a glance:** Likely benign · review: Single submitter · rsID rs1362231306 · 1 submitter · 1 linked condition · very rare (popmax 0.000701%, nfe)

## For patients & families {#patients}

This is a change in the EPM2A gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to progressive myoclonus epilepsy.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007140/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EPM2A](https://sugi.bio/atlas/gene/EPM2A/) |
| Protein change (HGVS p.) | p.Phe84= |
| Coding change (HGVS c.) | c.252C>T |
| MANE Select transcript | [NM_005670](https://www.ncbi.nlm.nih.gov/nuccore/NM_005670) |
| dbSNP | [rs1362231306](https://www.ncbi.nlm.nih.gov/snp/rs1362231306/) |
| Variant type | single nucleotide variant |
| Location | chr6:145735247-145735247 (GRCh38) |
| ClinVar | [VCV756722](https://www.ncbi.nlm.nih.gov/clinvar/variation/756722/) |

**All HGVS expressions:** `NC_000006.11:g.146056383G>A`, `NC_000006.12:g.145735247G>A`, `NG_012832.2:g.5609C>T`, `NM_001018041.2:c.252C>T`, `NM_001360057.2:c.252C>T`, `NM_001360064.2:c.-114+661C>T`, `NM_001360071.2:c.-418C>T`, `NM_001368129.2:c.-372C>T`, `NM_001368130.1:c.252C>T`, `NM_001368131.1:c.-116C>T`, `NM_005670.4:c.252C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 9.035, GERP 0.814, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 15.65**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.21 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000701%** (nfe) · FAF95 0.000301% · FAF99 0.000218% · 8/1,141,842 in the highest group · 8/1,538,190 alleles overall — very rare (popmax 0.000701%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**EPM2A** population constraint: LOEUF 1.191, pLI 4.004e-07, missense-Z -0.9603. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Lafora disease** — Definitive (AR)

## Protein context {#protein}

Residue **84** lies in the 'disordered' region; the cbm20 domain; a UniProt-annotated variant site (in melf1; affects phosphatase activity and glycogen binding; disrupts the interaction with ppp1r3c); a β-strand.

AlphaFold model confidence (whole protein): pLDDT 34.25, 0% of residues very-high.

**2 experimental structure(s)** (PDB): [4R30](https://www.rcsb.org/structure/4R30), [4RKK](https://www.rcsb.org/structure/4RKK).

## What this gene does {#gene-function}

*Describes the biological roles of EPM2A (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** EPM2A's established molecular role includes protein serine/threonine phosphatase activity. p.Phe84= falls in the disordered region. In Reactome, EPM2A is annotated in disease pathway(s) including **Myoclonic epilepsy of Lafora**.

**Disease mechanism (Reactome):** EPM2A loss or alteration is curated in [Myoclonic epilepsy of Lafora](https://reactome.org/content/detail/R-HSA-3785653).

### Pathways affected {#pathways}

EPM2A participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Myoclonic epilepsy of Lafora](https://reactome.org/content/detail/R-HSA-3785653) | curated |
| [Glycogen synthesis](https://reactome.org/content/detail/R-HSA-3322077) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein serine/threonine phosphatase activity, protein tyrosine phosphatase activity, phosphatase activity, carbohydrate phosphatase activity, carbohydrate binding, protein homodimerization activity.

**Biological process:** positive regulation of macroautophagy, negative regulation of TOR signaling, glycogen metabolic process, protein dephosphorylation, negative regulation of phosphatase activity, dephosphorylation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-19.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-03-19 |

## Associated conditions {#conditions}

[progressive myoclonus epilepsy](https://sugi.bio/atlas/disease/progressive-myoclonus-epilepsy/).

**Reported phenotype names (ClinVar):** Progressive myoclonic epilepsy, Myoclonic Epilepsies, Progressive, Familial progressive myoclonic epilepsy, Myoclonus epilepsy, Progressive myoclonus epilepsy.

## Same-residue context {#hotspot}

Residue **84** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [EPM2A p.Phe84Leu](/variant/epm2a-p-phe84leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related EPM2A variant pages (same residue, condition, or type): [EPM2A p.Phe84Leu](/variant/epm2a-p-phe84leu), [EPM2A c.301+1G>T](/variant/epm2a-c-301-plus-1g-t), [EPM2A c.302-1G>C](/variant/epm2a-c-302-minus-1g-c), [EPM2A c.302-2A>G](/variant/epm2a-c-302-minus-2a-g), [EPM2A p.Arg108Cys](/variant/epm2a-p-arg108cys), [EPM2A p.Arg171His](/variant/epm2a-p-arg171his), [EPM2A p.Arg241Ter](/variant/epm2a-p-arg241ter), [EPM2A p.Gly279Cys](/variant/epm2a-p-gly279cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 756722). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*