SGCA p.Ser82Arg
c.246C>A · rs1598265282 · VCV813953
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Likely Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PM2_Supporting PS3_Moderate PP4 PM3
Curation rationale (ClinGen, verbatim)
The NM_000023.4: c.246C>A variant in SGCA is a missense variant predicted to cause substitution of serine by arginine at amino acid 82, p.(Ser82Arg). This variant has been detected in at least four homozygous individuals with limb-girdle muscular dystrophy of Iranian ancestry (1 pt, ClinVar: SCV001164458.1; PMID: 39678382, 38374194, 32528171, 41315541) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness (PP4; PMID: 32528171, 41315541). In vitro assay in a heterologous cell system has demonstrated that this variant disrupts membrane localization of the sarcoglycan complex (PS3_Moderate, Washington University internal data). This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.504, which is below the threshold of 0.7 (PP3 not met). In summary, this variant meets the criteria to be classified as Likely 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; 04/29/2026): PM3, PP4, PS3_Moderate, PM2_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.5324 | ambiguous |
|---|---|---|
| REVEL | 0.504 | indeterminate |
| SaProt | LLR -9.20 | tolerated |
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP -0.55 | GERP -1, phastCons 0.028 |
| Regional constraint | o/e 0.91 | unconstrained · MANE · 9,393 bp · p 0.033 · regional, not allelic |
| Overall | ||
| CADD | 21.9 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- SGCA
- Protein
- p.Ser82Arg
- Coding
- c.246C>A
- MANE Select
- NM_000023
- dbSNP
- rs1598265282
- Type
- single nucleotide variant
- Location
- chr17:50167670 (GRCh38)
- Gene constraint
- LOEUF 1.273 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 80.15
Similar variants
- SGCA p.Ser82= Likely benign ★ same residue
- SGCA c.37+6T>C Pathogenic ★★★ same condition
- SGCA c.585-1G>A Pathogenic ★★★ same condition
- SGCA c.957-11C>G Likely pathogenic ★★★ same condition
- SGCA p.Ala107Val Likely pathogenic ★★★ ⚠ same condition
- SGCA p.Arg192Ter Pathogenic ★★★ same condition
- SGCA p.Arg221Cys Likely pathogenic ★★★ same condition
- SGCA p.Arg221Pro Likely 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/sgca-p-ser82arg (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown