EPM2A p.Ala46Pro
c.136G>C · rs374338349 · VCV162617
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 9 submitters
gnomAD v4.1
Common
common (popmax 13.5%, eas) — too common for a highly-penetrant pathogenic allele
Conditions
3
Inborn genetic diseases
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.25 | benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 2.9 | GERP -0.32, phastCons 0.12 |
| Regional constraint | o/e 1.04 | unconstrained · MANE · 108 kb · p 0.41 · regional, not allelic |
| Overall | ||
| CADD | 18.08 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
13.5%
East Asian · 1,706/12,684 alleles
Filtering AF
12.9%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 12.7%
Overall
0.384%
3,030/788,066 alleles · common
exomes 2,421/648,384 · genomes 609/139,682 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 13.5% | 7 |
| Finnishnot grpmax-eligible | 3.04% | 33 |
| Remaining individualsnot grpmax-eligible | 0.923% | 108 |
| South Asian | 0.854% | 117 |
| Ashkenazi Jewishnot grpmax-eligible | 0.446% | 224 |
| Middle Eastern | 0.115% | 869 |
| Admixed American | 0.0494% | 2,026 |
| African / African-American | 0.0443% | 2,257 |
| European (non-Finnish) | 0.0401% | 2,491 |
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.Ala46Pro
- Coding
- c.136G>C
- MANE Select
- NM_005670
- dbSNP
- rs374338349
- Type
- single nucleotide variant
- Location
- chr6:145735363 (GRCh38)
- Gene constraint
- LOEUF 1.191 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 34.25 · 2 PDB
- Residue 46
- the cbm20 domain; a UniProt-annotated variant site (does not affect glycogen binding)
Similar variants
- EPM2A p.Ala46Thr Uncertain significance ★★ same residue
- EPM2A p.Ala46= Likely benign ★ 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
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-ala46pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown