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These diseases are primarily caused by missense variants, but the limited predictability of their effect on protein maturation, complex formation, and transport has hindered reliable genotype\u2013phenotype correlations. This study aimed to establish accurate genotype\u2013phenotype correlations for LGMDR3, LGMDR4, and LGMDR5.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed the largest sarcoglycanopathy cohort to date (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009541). Clinical data, including age at symptom onset and loss of ambulation, were collected and used to define phenotype severity. Predictive models were developed considering the impact of non\u2010truncating variants on secondary structure, functional domains, evolutionary conservation, and intra\u2010complex protein\u2013protein interactions. Patients carrying two variants predicted to disrupt membrane trafficking were expected to present with severe phenotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>For LGMDR3, the best\u2010performing model classified variants affecting \u03b2\u2010sheets, cadherin\u2010like, and ATP\u2010binding domains as disruptive to membrane translocation, achieving 89% predictive power, 0.867 balanced accuracy, and 2.4% false\u2010negative rate (clinically severe patients who were wrongly classified by the model as mild). For LGMDR4 and LGMDR5, the best\u2010performing model involved conserved residues, \u03b2\u2010sheets, EGF\u2010like domain, and protein\u2013protein interactions\u2014reaching 80% predictive power, 0.689 balanced accuracy, and 3.1% false\u2010negative rate (LGMDR4), and 90% predictive power, 0.536 balanced accuracy, with no false negatives (LGMDR5). Additionally, we developed an open\u2010access predictive tool for clinical and research application.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>This study provides a robust genotype\u2013phenotype correlation for sarcoglycanopathies, improving prognosis, patient management, and clinical trial recruitment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70361","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T09:02:33Z","timestamp":1773910953000},"page":"1851-1865","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cracking the Code: Genotype\u2013Phenotype Correlation Models in Sarcoglycanopathies"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2956-2907","authenticated-orcid":false,"given":"Leonela","family":"Luce","sequence":"first","affiliation":[{"name":"John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute Newcastle University, and Newcastle Hospitals NHS Foundation Trust  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goknur Selen","family":"Kocak","sequence":"additional","affiliation":[{"name":"John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute Newcastle University, and Newcastle Hospitals NHS Foundation Trust  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5631-0030","authenticated-orcid":false,"given":"Jos\u00e9","family":"Verd\u00fa\u2010D\u00edaz","sequence":"additional","affiliation":[{"name":"John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute Newcastle University, and Newcastle Hospitals NHS Foundation Trust  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Alonso\u2010P\u00e9rez","sequence":"additional","affiliation":[{"name":"Neuromuscular Disease Unit, Neurology Department Hospital Universitario Nuestra Se\u00f1ora De Candelaria. Instituto De Investigaci\u00f3n Sanitaria De Canarias (IISC)  Tenerife Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristl G.","family":"Claeys","sequence":"additional","affiliation":[{"name":"Department of Neurology University Hospitals Leuven  Leuven Belgium"},{"name":"Laboratory for Muscle Diseases and Neuropathies, Department of Neurosciences KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Stojkovic","sequence":"additional","affiliation":[{"name":"Centre De R\u00e9f\u00e9rence Des Maladies Neuromusculaires Nord\/Est\/\u00cele\u2010De\u2010France, APHP, Groupe Hospitalier Piti\u00e9\u2010Salp\u00eatri\u00e8re Sorbonne Universit\u00e9  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gorka","family":"Fern\u00e1ndez\u2010Eulate","sequence":"additional","affiliation":[{"name":"Centre De R\u00e9f\u00e9rence Des Maladies Neuromusculaires Nord\/Est\/\u00cele\u2010De\u2010France, APHP, Groupe Hospitalier Piti\u00e9\u2010Salp\u00eatri\u00e8re Sorbonne Universit\u00e9  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Lafor\u00eat","sequence":"additional","affiliation":[{"name":"Centre De R\u00e9f\u00e9rence Des Maladies Neuromusculaires Nord\/Est\/\u00cele\u2010De\u2010France. APHP, CHU Raymond Poincar\u00e9, Garches Universit\u00e9 Paris\u2010Saclay  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najoua","family":"Miladi","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis University of Tunis El Manarrue Du Docteur Hassouna Ben Ayed  Tunis Tunisia"},{"name":"Laboratoire De Recherche En Neurologie p\u00e9diatrique (LR18SP04) \u00e0 L'institut National Mongi Ben Hamida De Neurologie  Tunis Tunisia"},{"name":"Maghreb Medical Center  Tunis Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filipe","family":"Di Pace","sequence":"additional","affiliation":[{"name":"Department of Neurology Faculdade De Medicina Da Universidade De S\u00e3o Paulo (FMUSP)  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5867-6359","authenticated-orcid":false,"given":"Cristiane Araujo Martins","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Neurology Faculdade De Medicina Da Universidade De S\u00e3o Paulo (FMUSP)  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edmar","family":"Zanoteli","sequence":"additional","affiliation":[{"name":"Department of Neurology Faculdade De Medicina Da Universidade De S\u00e3o Paulo (FMUSP)  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conrad C.","family":"Weihl","sequence":"additional","affiliation":[{"name":"Department of Neurology Washington University School of Medicine  Saint Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Straub","sequence":"additional","affiliation":[{"name":"John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute Newcastle University, and Newcastle Hospitals NHS Foundation Trust  Newcastle upon Tyne 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