# NM_005670.4(EPM2A):c.575T>C (p.Phe192Ser)

https://sugi.bio/variant/epm2a-p-phe192ser

## Summary

**EPM2A p.Phe192Ser (c.575T>C)** is classified **Uncertain significance** in EPM2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-27). Absent from gnomAD v4.1; Associated with progressive myoclonus epilepsy.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2128562619 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the EPM2A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Phe192Ser |
| Coding change (HGVS c.) | c.575T>C |
| MANE Select transcript | [NM_005670](https://www.ncbi.nlm.nih.gov/nuccore/NM_005670) |
| dbSNP | [rs2128562619](https://www.ncbi.nlm.nih.gov/snp/rs2128562619/) |
| Variant type | single nucleotide variant |
| Location | chr6:145635388-145635388 (GRCh38) |
| ClinVar | [VCV1362973](https://www.ncbi.nlm.nih.gov/clinvar/variation/1362973/) |

**All HGVS expressions:** `NC_000006.11:g.145956524A>G`, `NC_000006.12:g.145635388A>G`, `NG_012832.2:g.105468T>C`, `NM_001018041.2:c.575T>C`, `NM_001360057.2:c.477-7695T>C`, `NM_001360064.2:c.161T>C`, `NM_001360071.2:c.161T>C`, `NM_001368129.2:c.113T>C`, `NM_001368130.1:c.575T>C`, `NM_001368131.1:c.161T>C`, `NM_001368132.1:c.113T>C`, `NM_005670.4:c.575T>C`

## 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 11.102, GERP 1.95, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 32.0**. 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.*
- Regional missense constraint: **o/e 1.04** across the covering region of the MANE Select transcript (145,627,419–145,735,498), spanning 108,079 bp. Chi-square p 0.41. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **192** lies in the tyrosine-protein phosphatase domain.

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.Phe192Ser falls in the tyrosine-protein phosphatase domain. 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-27.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-27 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related EPM2A variant pages (same residue, condition, or type): [EPM2A p.Phe192=](/variant/epm2a-p-phe192), [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 2026-10-06); 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 1362973). 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.*