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Despite the importance of this synaptic network, cellular mechanisms dictating synapse formation during human neurodevelopment remain unclear. Long-distance trafficking by the microtubule motor KIF1A is crucial for synaptogenesis and downstream synapse maintenance. Mutations in KIF1A cause KIF1A-associated neurological disorder (KAND). We employed isogenic gene-edited human-induced pluripotent stem cell -derived neurons to assess the effects of disparate pathogenic mutations in KIF1A on synaptic trafficking and function. Null (p.C92*) and hypoactive (p.P305L) mutations delay neurite outgrowth, mislocalize synaptic cargoes, and decrease synapse density. Conversely, a hyperactive (p.R350G) mutation supports neurite outgrowth but causes aberrant motility of synaptic vesicle precursors and deficits in microtubule-dependent presynaptic patterning. Functional analysis of neuronal activity reveals delayed synaptic maturation in loss-of-function mutations (p.P305L, p.C92*) and precocious activity in the hyperactive p.R350G mutation. These data provide insights into how KIF1A mutations with distinct molecular-level impacts lead to significant downstream synaptic deficits in human neurons.<\/jats:p>","DOI":"10.1083\/jcb.202601034","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:21:02Z","timestamp":1786515662000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Pathogenic KIF1A variants differentially disrupt axonal trafficking and impede synaptic development"],"prefix":"10.1083","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6084-602X","authenticated-orcid":true,"given":"Jayne","family":"Aiken","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Pennsylvania Perelman School of Medicine 1 Department of Physiology, , Philadelphia, PA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/03k1gpj17","id-type":"ROR","asserted-by":"publisher"}],"name":"Colorado State University 2 Department of Biomedical Sciences, , Fort Collins, CO,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7550-2692","authenticated-orcid":true,"given":"Carris","family":"Borland","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Pennsylvania Perelman School of Medicine 1 Department of Physiology, , Philadelphia, PA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"Neuroscience Graduate Group, University of Pennsylvania Perelman School of Medicine 3 , Philadelphia, PA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3119-5368","authenticated-orcid":true,"given":"Nicolas","family":"Marotta","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Pennsylvania Perelman School of Medicine 1 Department of Physiology, , Philadelphia, PA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Epilepsy and Neurodevelopmental Disorders (ENDD), University of Pennsylvania Perelman School of Medicine 4 , Philadelphia, PA,","place":["USA"]},{"name":"Biochemistry, Biophysics, and Chemical Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3696-9131","authenticated-orcid":true,"given":"Benjamin L.","family":"Prosser","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Pennsylvania Perelman School of Medicine 1 Department of Physiology, , Philadelphia, PA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Epilepsy and Neurodevelopmental Disorders (ENDD), University of Pennsylvania Perelman School of Medicine 4 , Philadelphia, PA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00b30xv10","id-type":"ROR","asserted-by":"publisher"}],"name":"Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine 6 , Philadelphia, PA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5389-4114","authenticated-orcid":true,"given":"Erika L. 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