CAPN3 p.Leu74fs
c.219del · rs2141102673 · VCV1072479
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Likely Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting
Curation rationale (ClinGen, verbatim)
The NM_000070.3: c.219del p.(Leu74PhefsTer53) variant in CAPN3 is a frameshift 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 is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely 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, 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 | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 1 of 24 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 4.5 | GERP 1.7, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.
Variant & gene context
- Gene
- CAPN3
- Protein
- p.Leu74fs
- Coding
- c.219del
- MANE Select
- NM_000070
- dbSNP
- rs2141102673
- Type
- Deletion
- Location
- chr15:42360023 (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 74
- the calpain catalytic domain
Similar variants
- CAPN3 p.Leu74= Likely benign ★ same residue
- CAPN3 c.1194-2del Pathogenic ★★★ same condition
- CAPN3 p.Asp764fs Pathogenic ★★★ same condition
- CAPN3 p.Gln660_Ile661insTer Pathogenic ★★★ same condition
- CAPN3 p.Glu582fs Pathogenic ★★★ same condition
- CAPN3 p.Gly441fs Pathogenic ★★★ same condition
- CAPN3 p.Lys613fs Pathogenic ★★★ same condition
- CAPN3 p.Phe200_Leu204del 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-leu74fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown