CAPN3 p.Phe239fs
c.717del · rs776059672 · VCV284807
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting PP4_Strong PM3
Curation rationale (ClinGen, verbatim)
The NM_000070.3: c.717del (p.Phe239LeufsTer14) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 5/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in a homozygous state in six patients with signs of LGMD (1.0 pt; PMID: 10330340, 18073330, 17236769; PM3). At least one of the patients had a clinical diagnosis of LGMD and absent calpain-3 protein expression, which is highly specific for CAPN3-related LGMD (PMID: 17236769; PP4_Strong). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.1 is 0.00001 (6/1180006 European (non-Finnish) chromosomes), which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting, and therefore meets 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 (specifications v2.0.0; 04/29/2026): PVS1, PM3, PP4_Strong, 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 5 of 24 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 1.4 | GERP -2.2, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0011% | 91,080 |
| European (non-Finnish) | 0.000508% | 196,668 |
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.Phe239fs
- Coding
- c.717del
- MANE Select
- NM_000070
- dbSNP
- rs776059672
- Type
- Deletion
- Location
- chr15:42389007 (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 239
- the calpain catalytic domain; a β-strand
Similar variants
- 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.Leu74fs Likely 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-phe239fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown