CAPN3 p.Arg110fs
c.327_328dup · rs797045427 · VCV210563
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PVS1 PM3_Supporting PM2_Supporting PP4_Strong
Curation rationale (ClinGen, verbatim)
The NM_000070.3: c.327_328dup p.(Arg110ProfsTer18) variant 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 has been identified in at least two patients with features consistent with LGMD (PMID: 30564623, 1805549; LOVD CAPN3_000440), including in unconfirmed phase with a pathogenic variant (c.1993-1G>A, 0.5 pts, PMID: 30564623, LOVD Individual #00220608) (PM3_Supporting). At least one individual with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness as well as absent CAPN3 expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 18055493, LOVD Individual #00214565; PP4_Strong). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000076118 (74/1179616 European (non-Finnish) alleles), which is less than the VCEP threshold of 0.0001 (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 Limb Girdle Muscular Dystrophy Expert Panel (specification version 2.0.0; 03/12/2026): PVS1, PM3_Supporting, 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 2 of 24 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 0.82 | GERP -2.9, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.00627% | 15,941 |
| African / African-American | 0.00133% | 75,042 |
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.Arg110fs
- Coding
- c.327_328dup
- MANE Select
- NM_000070
- dbSNP
- rs797045427
- Type
- Duplication
- Location
- chr15:42384497 (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 110
- the calpain catalytic domain
Similar variants
- CAPN3 p.Arg110Ter Pathogenic ★★★ same residue
- CAPN3 p.Arg110Gln Likely benign ★★★ same residue
- CAPN3 p.Asn760fs Pathogenic ★★★ same condition
- CAPN3 p.Leu87fs 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-arg110fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown