SGCA p.Ile103Val
c.307A>G · rs370819630 · VCV284685
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PM2_Supporting PP4_Strong PM3_Strong PP1 PP3
Curation rationale (ClinGen, verbatim)
The NM_000023.4: c.307A>G variant in SGCA is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 103, p.(Ile103Val). This variant has been detected in five unrelated individuals with limb-girdle muscular dystrophy (PMID: 32528171, 30564623; Newcastle University, GRASP-LGMD Consortium internal data communication; LOVD SGCA_000155). Of those individuals, two were confirmed compound heterozygous for the variant and a pathogenic variant (c.229C>T p.(Arg77Cys), 1.0 pt, Newcastle University internal data communication; c.739G>A p.(Val247Met), 1.0 pt, PMID: 32528171, MYO-Seq study internal data communication). In at least three, individuals, the variant was reported in unconfirmed phase with a pathogenic variant (c.229C>T p.(Arg77Cys), 0.5 pts x2, PMID: 30564623, Newcastle University internal data communication; c.293G>A p.(Arg98His), 0.5 pts, PMID: 30564623, LOVD Individual #00219726) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic SGCA variant displayed progressive limb girdle muscle weakness and reduced alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PP4_Strong; PMID: 32528171). The variant has also been reported to segregate with autosomal recessive limb girdle muscular dystrophy in two affected siblings from one family (PP1; Newcastle University internal data communication). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.1 is 0.000048072 (44/1176834 European (non-Finnish) alleles), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, and therefore meets this criterion. The computational predictor REVEL gives a score of 0.826, which is above the threshold of 0.7, 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 2.0.0; 04/29/2026): PM3_Strong, PP4_Strong, PM2_Supporting, PP1, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.2347 | likely benign ⚠ discordant with ClinVar |
|---|---|---|
| REVEL | 0.826 | moderately pathogenic-leaning |
| SaProt | LLR -5.45 | tolerated |
| ⇒ REVEL calls this damaging; AlphaMissense and SaProt do not. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 9.2 | GERP 1.2, phastCons 1 |
| Regional constraint | o/e 0.91 | unconstrained · MANE · 9,393 bp · p 0.033 · regional, not allelic |
| Overall | ||
| CADD | 25.3 | 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 |
|---|---|---|
| Remaining individualsnot grpmax-eligible | 0.00643% | 15,556 |
| European (non-Finnish)grpmax | 0.00374% | 26,746 |
Remaining individuals 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.Ile103Val
- Coding
- c.307A>G
- MANE Select
- NM_000023
- dbSNP
- rs370819630
- Type
- single nucleotide variant
- Location
- chr17:50167731 (GRCh38)
- Gene constraint
- LOEUF 1.273 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 80.15
- Residue 103
- a UniProt-annotated variant site (in lgmdr3)
Similar variants
- SGCA p.Ile103Thr Pathogenic/Likely pathogenic ★★ same residue
- SGCA p.Ile103Phe 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
- SGCA p.Arg221Cys 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-ile103val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown