SGCA p.Arg77Cys
c.229C>T · rs28933693 · VCV9437
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PP1_Strong PS3_Supporting PM3_Strong PP3 PP4
Curation rationale (ClinGen, verbatim)
The NM_000023.4: c.229C>T variant in SGCA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 77 (p.Arg77Cys). This variant has been detected in at least 12 individuals with symptoms of limb girdle muscular dystrophy. Of those individuals, two were confirmed compound heterozygous for the variant and a pathogenic or likely pathogenic variant (c.850C>T, 2 pts, PMID: 12566530, LOVD Individual #0000223892), and at least two were homozygous for the variant (1 pt, PMID: 12566530, 23989969, 7663524, 37628638) (PM3_Strong). The variant has been reported to segregate with autosomal recessive limb girdle muscular dystrophy in 10 affected family members from five families (PP1_Strong; LOVD Individual #0000223892, PMID: 12566530, 7663524). At least one patient with this variant displayed progressive limb girdle muscle weakness and reduced alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PMID: 7663524; PP4) (capped with PP1_Strong). The filtering allele frequency of this variant is 0.0004392 (the lower threshold of the 95% CI of 62/112872 exome chromosomes) in the European (non-Finnish) population in gnomAD v2.1.1, which is lower than the ClinGen LGMD VCEP threshold (>0.0009) for BS1 (BS1, PM2_Supporting not met). In vitro assays have demonstrated this variant disrupts membrane localization of the sarcoglycan protein complex (PMID: 18535179; PS3_Supporting), and the computational predictor REVEL gives a score of 0.95, which exceeds the threshold of ≥0.70, evidence that correlates with impact to SGCA 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 1.0.0; 01/08/2025): PM3_Strong, PP1_Strong, PP4, PP3, PS3_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.2701 | likely benign ⚠ discordant with ClinVar |
|---|---|---|
| REVEL | 0.95 | strongly pathogenic-leaning |
| SaProt | LLR -11.85 | damaging |
| ⇒ REVEL and SaProt call this damaging; AlphaMissense does not. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 5.9 | GERP 1.2, phastCons 1 |
| Regional constraint | o/e 0.91 | unconstrained · MANE · 9,393 bp · p 0.033 · 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 |
|---|---|---|
| Finnishnot grpmax-eligible | 0.166% | 602 |
| European (non-Finnish)grpmax | 0.0515% | 1,941 |
| Remaining individualsnot grpmax-eligible | 0.0336% | 2,977 |
| Admixed American | 0.0167% | 6,004 |
| East Asian | 0.0111% | 8,976 |
| African / African-American | 0.0107% | 9,378 |
Finnish 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
- SGCA
- Protein
- p.Arg77Cys
- Coding
- c.229C>T
- MANE Select
- NM_000023
- dbSNP
- rs28933693
- Type
- single nucleotide variant
- Location
- chr17:50167653 (GRCh38)
- Gene constraint
- LOEUF 1.273 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 80.15
- Residue 77
- a UniProt-annotated variant site (in lgmdr3)
Similar variants
- SGCA p.Arg77His Uncertain significance ★★ ⚠ same residue
- SGCA p.Arg77= Likely benign ★ same residue
- SGCA p.Arg77fs Pathogenic/Likely pathogenic ★★ 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
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-arg77cys (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown