CAPN3 p.Glu323Ter
c.967G>T · rs750443041 · VCV620114
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.967G>T p.(Glu323Ter) variant in CAPN3, which is also known as p.(Glu323del), 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 trans with a likely pathogenic or pathogenic variant in an individual with limb girdle muscular dystrophy (c.146G>A p.(Arg49His), 1.0 pt, PMID: 17318636) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PMID: 17318636; PP4). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008802 (1/113610 exome alleles) in the European (non-Finnish) population, which is lower 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/SpliceAI carries the signal. | ||
| Consequence | nonsense (stop-gain) | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 7 of 24 |
| Splicing | ||
| SpliceAI | Δ0.43 | acceptor loss, 21 bp away · masked 0 · deltas |
| Pangolin | Δ0.32 | loss · gain 0.01 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 2.7, phastCons 1 |
| Overall | ||
| CADD | 45.0 | 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.Glu323Ter
- Coding
- c.967G>T
- MANE Select
- NM_000070
- dbSNP
- rs750443041
- Type
- single nucleotide variant
- Location
- chr15:42392660 (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 323
- the calpain catalytic domain
Similar variants
- CAPN3 p.Glu323fs Likely pathogenic ★ same residue
- 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
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-glu323ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown