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We report seven rare missense or in-frame microdeletion human\n                    <jats:italic>SARM1<\/jats:italic>\n                    variant alleles in patients with amyotrophic lateral sclerosis (ALS) or other motor nerve disorders that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activity of these seven variants is similar to that of SARM1 lacking the entire ARM domain and greatly exceeds the activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful, mild stress. Importantly, these strong gain-of-function alleles are completely patient-specific in the cohorts studied and show a highly significant association with disease at the single gene level. These findings of disease-associated coding variants that alter SARM1 function build on previously reported genome-wide significant association with ALS for a neighbouring, more common\n                    <jats:italic>SARM1<\/jats:italic>\n                    intragenic single nucleotide polymorphism (SNP) to support a contributory role of SARM1 in these disorders. A broad phenotypic heterogeneity and variable age-of-onset of disease among patients with these alleles also raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.\n                  <\/jats:p>","DOI":"10.7554\/elife.70905","type":"journal-article","created":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T07:15:12Z","timestamp":1637306112000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.70905","source":"Crossref","is-referenced-by-count":76,"title":["Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9510-7956","authenticated-orcid":true,"given":"Jonathan","family":"Gilley","sequence":"first","affiliation":[{"name":"John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1825-9331","authenticated-orcid":true,"given":"Oscar","family":"Jackson","sequence":"additional","affiliation":[{"name":"John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menelaos","family":"Pipis","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehrdad A","family":"Estiar","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, McGill University","place":["Montreal, Canada"]},{"name":"The Neuro (Montreal Neurological Institute-Hospital), McGill University","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ammar","family":"Al-Chalabi","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King\u2019s College London","place":["London, United Kingdom"]},{"name":"Department of Neurology, King's College Hospital, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt C","family":"Danzi","sequence":"additional","affiliation":[{"name":"Dr. John T. 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