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BACKGROUND: Hereditary spastic paraplegias (HSPs) are neurodegenerative disorders characterized by lower-limb spasticity. Pathogenic variants in CPT1C have been implicated in HSP.OBJECTIVE: The objective of this study was to assess whether CPT1C loss-of-function (LOF) variants are causally associated with HSP.METHODS: We analyzed whole-genome sequencing data from UK Biobank (UKBB), whole-exome sequencing data from a Canadian HSP cohort (Can-HSP), and genetic data from the GENESIS cohort-a large international cohort of patients with rare hereditary diseases, including HSP.RESULTS: Among >170 CPT1C LOF carriers in the UKBB (n = 150,119), none exhibited HSP phenotypes. Among 585 HSP patients from Can-HSP, we did not find patients with CPT1C LOF variants. In the GENESIS cohort (n = 21,217), three individuals carrying CPT1C LOF variants were also diagnosed with HSP; however, all three also carry pathogenic variants in established HSP-associated genes.CONCLUSIONS: Our study does not support a causal role for CPT1C LOF variants in HSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.