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Using KIF1A-associated neurological disorder (KAND) as a model system, we integrated single-molecule biophysical phenotyping of 91 pathogenic variants with longitudinal clinical characterization of 343 patients. Vineland Adaptive Behavior Scales (VABS) Adaptive Behavior Composite (ABC) and Growth Scales identified two divergent trajectories emerging after age 10: a stable group and a declining group characterized by seizures, abnormal EEGs, and optic nerve atrophy. A framework combining biophysical parameters, computational pathogenicity scores, and clinical variables classified patients as stable versus declining with AUC 0.834 and predicted VABS ABC scores with R\u00b2 = 0.484 under leave-one-out cross-validation. For newly identified KIF1A variants, this approach offers a prognostic tool and a stratification strategy for clinical trials. Because kinesin motor function is mechanistically conserved, the framework may generalize to other kinesinopathies and to monogenic disorders amenable to quantitative functional assays.<\/jats:p>","DOI":"10.64898\/2026.09.10.26362467","type":"posted-content","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:40:29Z","timestamp":1789623629000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrating Single-Molecule Variant Phenotyping with Clinical Features Predicts Outcomes in KIF1A-Associated Neurological Disorder"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7447-1484","authenticated-orcid":false,"given":"Lu","family":"Rao","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6607-7716","authenticated-orcid":false,"given":"Jessica","family":"Waxler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8693-9720","authenticated-orcid":false,"given":"Candace","family":"Cameron","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Tam","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Columbia University, New York, NY 10027"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2073-5050","authenticated-orcid":false,"given":"Charles A.","family":"LeDuc","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1299-5979","authenticated-orcid":false,"given":"Yufeng","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032"},{"name":"Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8346-5473","authenticated-orcid":false,"given":"Arne","family":"Gennerich","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3438-5685","authenticated-orcid":false,"given":"Wendy K.","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"7","key":"2026092102351035000_2026.09.10.26362467v1.1","doi-asserted-by":"crossref","first-page":"101125","DOI":"10.1016\/j.gim.2024.101125","article-title":"Homozygous missense variants in YKT6 result in loss of function and are associated with developmental delay, with or without severe infantile liver disease and risk for hepatocellular carcinoma","volume":"26","year":"2024","journal-title":"Genet Med"},{"key":"2026092102351035000_2026.09.10.26362467v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3046"},{"key":"2026092102351035000_2026.09.10.26362467v1.3","doi-asserted-by":"crossref","unstructured":"Boyle, L. , et al., Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder. 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