CAPN3 p.Arg748Ter
c.2242C>T · rs768090444 · VCV283259
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PVS1 PP4_Moderate PM3
Curation rationale (ClinGen, verbatim)
The NM_000070.3: c.2242C>T p.(Arg748Ter) variant in CAPN3, which is also known as p.(Arg748del), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 21/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. mRNA analysis demonstrated reduced expression of the transcript containing the variant, consistent with nonsense mediated decay (PMID: 17157502) (PVS1). This variant has been detected in at least six individuals reported to have autosomal recessive LGMD (PMID: 25214167, 12461690, 16971480, 17157502, 18055493; Washington University internal clinic data communication). In at least one case, the variant was identified in unknown phase with a pathogenic variant (c.1468C>T p.(Arg490Trp), 0.5 pts, PMID: 16971480), and in at least two cases, the variant was identified in trans with a second CAPN3 variant not yet curated by the VCEP and considered VUS (0.5 pts, PMID: 12461690, 17157502) (PM3). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy and displayed reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID: 16971480). The filtering allele frequency of the variant is 0.000114 for European (non-Finnish) genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 3/68008), which is more than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion 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 LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4_Moderate.
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 21 of 24 |
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 2.2 | GERP 1.9, phastCons 1 |
| 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
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,474 |
| South Asiangrpmax | 0.0011% | 91,028 |
| European (non-Finnish) | 0.00102% | 98,322 |
Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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.Arg748Ter
- Coding
- c.2242C>T
- MANE Select
- NM_000070
- dbSNP
- rs768090444
- Type
- single nucleotide variant
- Location
- chr15:42410645 (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 748
- the 'domain iv' region; a UniProt-annotated variant site (in lgmdr1); an α-helix; the ef-hand 3 domain
Similar variants
- CAPN3 p.Arg748Gln Pathogenic ★★★ same residue
- CAPN3 p.Arg748Gly Pathogenic ★ same residue
- CAPN3 p.Arg748Leu Uncertain significance ★ ⚠ same residue
- CAPN3 p.Arg748= Likely benign ★ 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
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-arg748ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown