{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:44:12Z","timestamp":1783489452944,"version":"3.55.0"},"posted":{"date-parts":[[2026,6,26]]},"group-title":"Neurology","reference-count":38,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chief Scientist Office","award":["SCAF\/18\/01"],"award-info":[{"award-number":["SCAF\/18\/01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Pathogenic variants in leucine-rich repeat kinase 2 (\n                  <jats:italic>LRRK2<\/jats:italic>\n                  )\n                  <jats:sup>1<\/jats:sup>\n                  are among the most frequent monogenic causes of Parkinson\u2019s disease (PD)\n                  <jats:sup>2<\/jats:sup>\n                  and act through a gain-of-function mechanism of increased kinase activity.\n                  <jats:italic>LRRK2<\/jats:italic>\n                  -targeted therapies are in clinical development, but interpretation of the rapidly expanding catalogue of rare\n                  <jats:italic>LRRK2<\/jats:italic>\n                  variants remains a barrier to translation. Here, we present functionally annotated data on &gt;350\n                  <jats:italic>LRRK2<\/jats:italic>\n                  coding variants using a standardized cellular assay with Rab10 phosphorylation as a readout of kinase activity and integrated these data with curated genetic and clinical annotations from the Movement Disorders Society Genetic Mutation Database (MDSGene). Variants differed in activation magnitude, ranging from modest increases (e.g., p.G2019S) to strongly activating substitutions such as p.Y1699C or p.L1795F. Activating variants occurred across the full length of LRRK2, although the largest effects clustered within the ROC\u2013COR regulatory hub, where structural analysis identified subdomains forming an allosteric scaffold controlling kinase output. All known\/established pathogenic variants showed increased activity, whereas benign and likely benign variants remained within the wild-type range. Functional effect sizes correlated with pathway activation in patient-derived immune cells, altogether providing a framework for ACMG-based variant interpretation in which kinase activation can support PS3 functional evidence for reclassification of variants.\n                <\/jats:p>","DOI":"10.64898\/2026.06.17.26355034","type":"posted-content","created":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T03:05:10Z","timestamp":1782529510000},"source":"Crossref","is-referenced-by-count":1,"title":["Large-scale functional annotation establishes a reference framework for human\n                  <i>LRRK2<\/i>\n                  variants"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5969-6215","authenticated-orcid":false,"given":"Anthea","family":"Cheung","sequence":"first","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU), Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1124-8699","authenticated-orcid":false,"given":"Neringa","family":"Pratuseviciute","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU), Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1356-4560","authenticated-orcid":false,"given":"Kirsten","family":"Black","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU), Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4978-7671","authenticated-orcid":false,"given":"Pawel","family":"Lis","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU), Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2964-6070","authenticated-orcid":false,"given":"Toan","family":"Phung","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU), Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5530-7675","authenticated-orcid":false,"given":"Melanie","family":"Cavin","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU), Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3001-1886","authenticated-orcid":false,"given":"Gabriel","family":"Morel","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU), Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Saari","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU), Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8201-5406","authenticated-orcid":false,"given":"Vincent","family":"Huin","sequence":"additional","affiliation":[{"name":"University of Lille, Inserm, CHU Lille, U1172 - LilNCog (JPARC) - Lille Neurosciences & Cognition, F-59000 Lille, France"},{"name":"Lille University Hospital, Department of Toxicology and Genopathies, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3767-6376","authenticated-orcid":false,"given":"Simone","family":"Zittel-Dirks","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4600-6630","authenticated-orcid":false,"given":"Francesca","family":"Tonelli","sequence":"additional","affiliation":[{"name":"Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU), Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Riebenbauer","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of T\u00fcbingen, T\u00fcbingen, 72076, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1069-1146","authenticated-orcid":false,"given":"Thomas","family":"Gasser","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of T\u00fcbingen, T\u00fcbingen, 72076, Germany"},{"name":"Centre for Neurology, University Clinic T\u00fcbingen, T\u00fcbingen, 72076, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7326-6270","authenticated-orcid":false,"given":"Javier","family":"Ruiz-Martinez","sequence":"additional","affiliation":[{"name":"Department of Neurology, Donostia University Hospital, Biogipuzkoa Health Research Institute, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), San Sebasti\u00e1n ES 20014, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Global Parkinson\u2019s Genetics Program (GP2)","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5473-3774","authenticated-orcid":false,"given":"Huw R.","family":"Morris","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK"},{"name":"UCL Movement Disorders Centre, University College London, London WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7162-9821","authenticated-orcid":false,"given":"Lara M","family":"Lange","sequence":"additional","affiliation":[{"name":"Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, and National Institutes of Health, Bethesda, MD 20892, 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