CAPN3 p.Glu343Ter
c.1027G>T · rs766334893 · VCV497182
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting PP4 PM3
Curation rationale (ClinGen, verbatim)
The NM_000070.3: c.1027G>T (p.Glu343Ter) variant in CAPN3, which is also known as p.(Glu343del), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 7/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least five individuals with features of limb girdle muscular dystrophy (PMID: 34628793, 30564623; LOVD CAPN3_000602; ClinVar SCV000953543.3 internal data communication), including in unknown phase with a pathogenic variant in two cases (c.1468C>T p.(Arg490Trp), 1.0 pt, PMID: 30564623; LOVD Individual #00222348; ClinVar SCV000953543.3 internal data communication) (PM3). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy (PP4). The highest population minor allele frequency of the variant is 0.00005787 (2/34560 exome chromosomes) in the Admixed American population of gnomAD v2.1.1, which is less than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4, PM2_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | nonsense (stop-gain) | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 7 of 24 |
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 1.9, phastCons 1 |
| Overall | ||
| CADD | 57.0 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
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
- CAPN3
- Protein
- p.Glu343Ter
- Coding
- c.1027G>T
- MANE Select
- NM_000070
- dbSNP
- rs766334893
- Type
- single nucleotide variant
- Location
- chr15:42392720 (GRCh38)
- Gene constraint
- LOEUF 0.896 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 79.18 · 5 PDB
- Residue 343
- the calpain catalytic domain; a β-strand
Similar variants
- CAPN3 c.1115+5G>C Pathogenic ★★★ same condition
- CAPN3 c.1194-2A>G Pathogenic ★★★ same condition
- CAPN3 c.1194-9A>G Pathogenic ★★★ same condition
- CAPN3 c.1746-20C>G Pathogenic ★★★ same condition
- CAPN3 c.1993-1G>A Pathogenic ★★★ same condition
- CAPN3 c.499-1G>A Pathogenic ★★★ same condition
- CAPN3 p.Ala702Val Pathogenic ★★★ same condition
- CAPN3 p.Ala798Glu 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/capn3-p-glu343ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown