# NM_005670.4(EPM2A):c.102G>C (p.Pro34=)

https://sugi.bio/variant/epm2a-p-pro34

## Summary

**EPM2A p.Pro34= (c.102G>C)** is classified **Likely benign** in EPM2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-06). Very rare (popmax 0.00203%, nfe); Associated with progressive myoclonus epilepsy.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs1014133463 · 3 submitters · 1 linked condition · very rare (popmax 0.00203%, 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 3 submitters, 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.Pro34= |
| Coding change (HGVS c.) | c.102G>C |
| dbSNP | [rs1014133463](https://www.ncbi.nlm.nih.gov/snp/rs1014133463/) |
| Variant type | single nucleotide variant |
| Location | chr6:145735397-145735397 (GRCh38) |
| ClinVar | [VCV511540](https://www.ncbi.nlm.nih.gov/clinvar/variation/511540/) |

**All HGVS expressions:** `NC_000006.11:g.146056533C>G`, `NC_000006.12:g.145735397C>G`, `NG_012832.2:g.5459G>C`, `NM_001018041.2:c.102G>C`, `NM_001360057.2:c.102G>C`, `NM_001360064.2:c.-114+511G>C`, `NM_001360071.2:c.-568G>C`, `NM_001368129.2:c.-522G>C`, `NM_001368130.1:c.102G>C`, `NM_001368131.1:c.-266G>C`, `NM_005670.4:c.102G>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 1.926, GERP 0.638, phastCons 0.962 — weakly conserved position
- CADD: **PHRED 12.52**. 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: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.00203%** (nfe) · FAF95 0.00132% · FAF99 0.00108% · 20/987,070 in the highest group · 22/1,235,058 alleles overall — very rare (popmax 0.00203%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00456% | 21,911 |
| European (non-Finnish) (grpmax) | 0.00203% | 49,353 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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.*

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-06.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2017–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2017-08-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-01-06 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Progressive myoclonic epilepsy, not specified, AllHighlyPenetrant, Myoclonic Epilepsies, Progressive, Progressive myoclonus epilepsy, Familial progressive myoclonic epilepsy, Myoclonus epilepsy.

### 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 2026-07-14); 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 511540). 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.*