CAPN3 p.Arg748Gln
c.2243G>A · rs587780290 · VCV128570
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PP4_Strong PM3_Strong PP1 PP3
Curation rationale (ClinGen, verbatim)
The NM_000070.3: c.2243G>A variant in CAPN3 is a missense variant expected to result in the substitution of arginine with glutamine at amino acid 748, p.(Arg748Gln). Across a selection of the available literature, this variant has been reported in at least 16 individuals with features consistent with LGMD (PMID: 32994280, 22443334, 15689361, 30838351; LOVD CAPN3_000028), including in a homozygous state without reported consanguinity in at least six unrelated patients of Chinese, Turkish, and Spanish ancestry (1.0 pt; PMID: 32994280, 22443334, 15689361, 30838351). It has also been identified in unconfirmed phase with a pathogenic variant in at least two patients (c.2120A>G p.(Asp707Gly), 0.5 pts, PMID: 32994280, LOVD Individual #00311286; c.2362_2363delinsTCATCT p.(Arg788SerfsTer14), 0.5 pts, PMID: 15689361, LOVD Individual #00214354) (PM3_Strong). This variant was identified in a homozygous state in one individual with both progressive limb girdle muscle weakness and absent calpain-3 protein expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 22443334; PP4_Strong). In addition, this variant has also been shown to co-segregate with autosomal recessive LGMD in one affected family member (PMID: 30838351; PP1). The upper bound of the 95% confidence interval (95% CI) of the highest population variant allele frequency in gnomAD v4.1.0 is 0.0002408 (8/59942 Admixed American chromosomes), which is higher than the threshold of 0.0001 (PM2_Supporting not met). This variant had no effect on splicing in a mini-gene assay (PMID: 32668095), but a deleterious effect of the amino acid change cannot be excluded (BP7_Strong not met), and the computational predictor REVEL gives a score of 0.724, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3). 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 2.0.0; 03/12/2026): PM3_Strong, PP4_Strong, PP1, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.5289 | ambiguous |
|---|---|---|
| REVEL | 0.724 | pathogenic-leaning |
| SaProt | LLR -13.36 | damaging |
| ⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 0.65, phastCons 1 |
| Regional constraint | o/e 0.96 | unconstrained · MANE · 52 kb · p 0.21 · regional, not allelic |
| Overall | ||
| CADD | 34.0 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0133% | 7,493 |
| East Asian | 0.00223% | 44,880 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,478 |
| African / African-American | 0.00134% | 74,846 |
| European (non-Finnish) | 0.000678% | 147,489 |
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.Arg748Gln
- Coding
- c.2243G>A
- MANE Select
- NM_000070
- dbSNP
- rs587780290
- Type
- single nucleotide variant
- Location
- chr15:42410646 (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.Arg748Ter 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-arg748gln (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown