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Given the recent authorization of\n                      <jats:italic>SOD1<\/jats:italic>\n                      \u2010targeted antisense oligonucleotides for\n                      <jats:italic>SOD1<\/jats:italic>\n                      \u2010ALS, prompt screening for\n                      <jats:italic>SOD1<\/jats:italic>\n                      mutations in patients with ALS patients is highly recommended. Large\u2010scale genomic analysis could inform on the population\u2010based prevalence of\n                      <jats:italic>SOD1<\/jats:italic>\n                      mutation carriers, who would potentially benefit from treatment. We aim to determine the number of people with pathogenic\n                      <jats:italic>SOD1<\/jats:italic>\n                      variants in the UK Biobank (UKB), to address a critical gap between clinical and genetic prevalence of\n                      <jats:italic>SOD1<\/jats:italic>\n                      \u2010ALS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed\n                      <jats:italic>SOD1<\/jats:italic>\n                      variants within exome sequencing data from 470,000 individuals aged over 40\u2009years. Pathogenicity was evaluated using referenced databases and American College of Medical Genetics and Genomics (ACMG) guidelines. Leveraging the UKB carrier frequency and age at onset data, we estimated the genetic prevalence of\n                      <jats:italic>SOD1<\/jats:italic>\n                      \u2010ALS. We examined factors that may influence penetrance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 122 individuals with monoallelic\n                      <jats:italic>SOD1<\/jats:italic>\n                      coding variants, 93.4% of whom were asymptomatic. Additionally, the low\u2010penetrance p.Asp91Ala variant was observed in heterozygosis in 535 subjects, whereas it was never found in homozygosis. Excluding this variant, the expected number of people developing\n                      <jats:italic>SOD1<\/jats:italic>\n                      \u2010ALS is 1.04:100,000 in the UK population, 4 times higher than clinically reported figures. Symptomatic carriers had significantly increased levels of serum neurofilament at baseline. Age\u2010related penetrance was higher in non\u2010p.Asp91Ala carriers versus p.Asp91Ala carriers. Long\u2010term survivor status was associated with p.Asp91Ala genotype, older age, and lower neurofilament levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Incomplete and age\u2010related penetrance, along with underascertainment due to disease heterogeneity and limitations in data collection, likely account for the reduced number of symptomatic patients identified. Our findings highlight the need to identify genetic and environmental factors, as well as biological indicators, able to influence disease penetrance and phenoconversion risk in presymptomatic carriers and to predict treatment response in patients. ANN NEUROL 2026;99:1502\u20131515<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78195","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T07:51:11Z","timestamp":1773906671000},"page":"1502-1515","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["High Prevalence of\n                    <scp>\n                      <i>SOD1<\/i>\n                    <\/scp>\n                    Pathogenic Variants in the\n                    <scp>UK<\/scp>\n                    Biobank: Implications for Early Intervention in Amyotrophic Lateral Sclerosis"],"prefix":"10.1002","volume":"99","author":[{"given":"Delia","family":"Gagliardi","sequence":"first","affiliation":[{"name":"Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit  Milan 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Department of Pathophysiology and Transplantation University of Milan  Milan Italy"},{"name":"Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Disease Unit  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1383-5248","authenticated-orcid":false,"given":"Giacomo Pietro","family":"Comi","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit  Milan Italy"},{"name":"Dino Ferrari Center, Department of Pathophysiology and Transplantation University of Milan  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Fratta","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology University College London  London UK"},{"name":"The Francis Crick Institute  London 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