SGCA p.Val242Phe
c.724G>T · rs200166783 · VCV471337
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PP4_Moderate PM2_Supporting PM3_VeryStrong PS3_Moderate PP1_Moderate PP3
Curation rationale (ClinGen, verbatim)
The NM_000023.4: c.724G>T variant in SGCA is a missense variant predicted to cause substitution of valine by phenylalanine at amino acid 242, p.(Val242Phe). This variant has been detected in at least nine individuals with limb-girdle muscular dystrophy (PMID: 10842281, 12566530, 32875335, 31268554; LOVD Individual #00133494), including in a homozygous state in two unrelated patients, one of whom had known familial consanguinity (0.75 pts, PMID: 12566530, 31268554). In seven patients, it was reported in unconfirmed phase with a pathogenic variant (c.229C>T p.(Arg77Cys), c.739G>A p.(Val247Met), c.850C>T p.(Arg284Cys); 3.5 pts; PMID: 10842281, 12566530, 32875335, 31268554; LOVD: #00133494) (PM3_Very Strong). It has been reported to segregate with autosomal recessive LGMD in two affected family members from one family (PP1_Moderate; PMID: 10842281,12566530). At least one patient homozygous for this variant displayed progressive limb girdle muscle weakness and absent alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PP4_Moderate, capped with PP1_Moderate; PMID: 12566530). The highest variant allele frequency in gnomAD v4.1.1 is 0.000079054 (1/60006 Admixed American alleles), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, and therefore meets this criterion. An in vitro assay in a heterologous cell system has demonstrated that this variant disrupts membrane localization of the sarcoglycan complex, indicating disruption of protein function (PS3_Moderate, Washington University internal data). The computational predictor REVEL also gives a score of 0.729, 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; 05/01/2026): PM3_Very Strong, PP1_Moderate, PP4_Moderate, PM2_Supporting, PS3_Moderate, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.4656 | ambiguous |
|---|---|---|
| REVEL | 0.729 | pathogenic-leaning |
| SaProt | LLR -10.39 | damaging |
| ⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 0.6 | GERP -3, phastCons 0.046 |
| Regional constraint | o/e 0.91 | unconstrained · MANE · 9,393 bp · p 0.033 · regional, not allelic |
| Overall | ||
| CADD | 19.47 | 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 | 0.00167% | 60,006 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,494 |
| European (non-Finnish) | 8.48e-05% | 1,179,869 |
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.Val242Phe
- Coding
- c.724G>T
- MANE Select
- NM_000023
- dbSNP
- rs200166783
- Type
- single nucleotide variant
- Location
- chr17:50169231 (GRCh38)
- Gene constraint
- LOEUF 1.273 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 80.15
- Residue 242
- a UniProt-annotated variant site (in lgmdr3)
Similar variants
- SGCA p.Val242Ala Likely pathogenic ★★ ⚠ same residue
- SGCA p.Val242Ile Uncertain significance ★★ ⚠ 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-val242phe (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown