CAPN3 p.Leu87fs
c.258dup · rs753360208 · VCV284122
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PVS1 PP4 PM3
Curation rationale (ClinGen, verbatim)
The NM_000070.3: c.258dup p.(Leu87SerfsTer4) variant in CAPN3 is a frameshift variant expected to cause a premature stop codon in biologically relevant exon 1/24, 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 at least three individuals with a clinical diagnosis or suspicion of LGMD without reported familial consanguinity (1.0 pt; PMID: 16650086, 30564623; LOVD CAPN3_000380) (PM3, PP4). The highest frequency of this variant in gnomAD v4.1.0 is 0.0002135 in the African/African American population (16/74948 alleles), which is greater than the LGMD VCEP threshold of 0.0001 (PM2_Supporting not met). 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 Limb Girdle Muscular Dystrophy Expert Panel (specifications version 2.0.0; 02/18/2026): PVS1, PM3, PP4.
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 7.7 | GERP 2.7, phastCons 1 |
| Overall | ||
| CADD | 34.0 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0213% | 4,684 |
| Admixed American | 0.00167% | 60,008 |
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.Leu87fs
- Coding
- c.258dup
- MANE Select
- NM_000070
- dbSNP
- rs753360208
- Type
- Duplication
- Location
- chr15:42360062 (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 87
- the calpain catalytic domain; an α-helix
Similar variants
- CAPN3 p.Leu87Val Uncertain significance ★★ ⚠ same residue
- CAPN3 p.Leu87Phe Likely pathogenic ★ same residue
- CAPN3 p.Arg110fs Pathogenic ★★★ same condition
- CAPN3 p.Asn760fs Pathogenic ★★★ same condition
- CAPN3 p.Pro245_Ser246insTer Pathogenic ★★★ same condition
- CAPN3 p.Tyr75fs Pathogenic ★★★ same condition
- CAPN3 c.2115+1_2115+2dup Likely pathogenic ★★ same condition
- CAPN3 p.Arg289fs 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-leu87fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown