Comprehensive Mapping of SGCA Variant Effects Reveals Domain-Specific Constraints Relevant to Sarcoglycanopathies
- 1Yale University School of Medicine
Abstract
Pathogenic variants in SGCA, encoding -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. -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 -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.
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BibTeX
@misc{huang2026comprehensive,
title = {{Comprehensive Mapping of SGCA Variant Effects Reveals Domain-Specific Constraints Relevant to Sarcoglycanopathies}},
author = {S. Huang and K. Ng and Y. Lu and Z. Xie and C. Hu and B. Zhu and W. Zhu and A. Lek and Y. Yang and S. Kim and K. Ma and M. Lek},
howpublished = {bioRxiv},
year = {2026},
month = jul,
doi = {10.64898/2026.07.22.740214},
url = {https://www.biorxiv.org/content/10.64898/2026.07.22.740214v2},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Comprehensive Mapping of SGCA Variant Effects Reveals Domain-Specific Constraints Relevant to Sarcoglycanopathies
AU - S. Huang
AU - K. Ng
AU - Y. Lu
AU - Z. Xie
AU - C. Hu
AU - B. Zhu
AU - W. Zhu
AU - A. Lek
AU - Y. Yang
AU - S. Kim
AU - K. Ma
AU - M. Lek
PY - 2026
DA - 2026/07/22
PB - bioRxiv
DO - 10.64898/2026.07.22.740214
UR - https://www.biorxiv.org/content/10.64898/2026.07.22.740214v2
AB - Pathogenic variants in SGCA, encoding -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. -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 -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.
ER -