Comprehensive Mapping of SGCA Variant Effects Reveals Domain-Specific Constraints Relevant to Sarcoglycanopathies
Year: 2026
Type: preprint
Abstract: Pathogenic variants in SGCA , encoding α-sarcoglycan, cause an autosomal recessive limb-girdle muscular dystrophy, LGMDR3/2D, yet clinical interpretation of SGCA variants remains challenging due to the high prevalence of rare missense variants. α-sarcoglycan is an essential component of the sarcoglycan complex at the muscle cell membrane, and pathogenic variants frequently impair its membrane localization. Here, we systematically assess the effects of all possible single-nucleotide variants across the SGCA coding sequence using a saturation mutagenesis-based experimental assay that quantifies α-sarcoglycan surface expression. We generate a comprehensive functional atlas that distinguishes tolerated and damaging variants, aligning with independent genetic and clinical evidence, and reveals domain-specific properties of the cytoplasmic region, in which C-terminal truncating variants retain membrane localization, suggesting possible pathogenic mechanisms beyond impaired trafficking. This work provides a scalable functional framework to support genetic diagnosis and variant interpretation in sarcoglycanopathies. Graphical Abstract Schematic overview of saturation mutagenesis-based functional mapping of SGCA .
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7171413016