CAPN3 p.Arg110Ter
c.328C>T · rs121434545 · VCV17615
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PVS1 PP4_Moderate PM2_Supporting PP1
Curation rationale (ClinGen, verbatim)
The NM_000070.3: c.328C>T p.(Arg110Ter) variant in CAPN3 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 2/24, 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 second CAPN3 variant in at least three unrelated individuals with LGMD (PMID: 26677118, 18854869). At least one patient with this variant displayed progressive limb girdle muscle weakness and reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID: 18854869). The variant has also been reported to co-segregate with the disease in one affected family member (PP1; PMID: 26677118). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008793 (1/113722 exome alleles) in the European (non-Finnish) population, which is less than the VCEP threshold (≤0.0001) (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; 01/07/2025): PVS1, PP4_Moderate, PP1, 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 2 of 24 |
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 1.4 | GERP -2.5, phastCons 0.4 |
| Overall | ||
| CADD | 38.0 | 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.Arg110Ter
- Coding
- c.328C>T
- MANE Select
- NM_000070
- dbSNP
- rs121434545
- Type
- single nucleotide variant
- Location
- chr15:42384501 (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 110
- the calpain catalytic domain
Similar variants
- CAPN3 p.Arg110Gln Likely benign ★★★ same residue
- CAPN3 p.Arg110fs 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
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-arg110ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown