CAPN3 p.Arg788fs
c.2362_2363delinsTCATCT · rs1555423217 · VCV17618
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PVS1_Moderate PM2_Supporting PP4_Strong PM3_Strong PP1
Curation rationale (ClinGen, verbatim)
The NM_000070.3: c.2362_2363delinsTCATCT p.(Arg788SerfsTer14) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 23/24 that may cause loss of function of the protein, however, it is predicted to escape nonsense mediated decay and remove <10% of the protein (PVS1_Moderate). This variant has been detected in at least 30 individuals with limb girdle muscular dystrophy, including in a homozygous state in one patient (0.5 pts, PMID: 18337726), in trans with a pathogenic variant in at least one patient (c.643_663del p.(Ser215_Gly221del), 1.0 pt, PMID: 9150160), and in unknown phase with a pathogenic variant (c.223dup p.(Tyr75LeufsTer5), 0.5 pts, PMID: 30564623, LOVD Individual #00220184) (PM3_Strong). At least one patient with this variant displayed a clinical suspicion of limb girdle muscular dystrophy and absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 18337726). The variant has also been reported to segregate with LGMD in one affected family member (PP1; PMID: 9150160). 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 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_Moderate, PM3_Strong, PP4_Strong, 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 | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 22 of 24 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 3.6 | GERP 1.8, 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.Arg788fs
- Coding
- c.2362_2363delinsTCATCT
- MANE Select
- NM_000070
- dbSNP
- rs1555423217
- Type
- Indel
- Location
- chr15:42410982 (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 788
- the 'domain iv' region; an α-helix; the ef-hand 4 domain
Similar variants
- CAPN3 p.Arg788Lys Uncertain significance ★ ⚠ same residue
- CAPN3 p.Arg788= Likely benign ★ same residue
- CAPN3 p.Asp295fs Pathogenic ★★★ same condition
- CAPN3 p.Arg490fs Pathogenic/Likely pathogenic ★★ same condition
- CAPN3 p.Lys71fs Pathogenic/Likely pathogenic ★★ same condition
- CAPN3 p.Arg788Met Uncertain significance ★★ ⚠ same residue
- CAPN3 p.Asp753fs Pathogenic ★ same condition
- CAPN3 p.Lys659_Gln660delinsAsnTer 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-arg788fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown