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Summary Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion of ALS risk variants within the non-coding genome, but further characterization has been limited by lack of appropriate tools. By designing and applying a pipeline to identify pathogenic genetic variation within enhancer elements responsible for regulating gene expression, we identify disease-associated variation within CAV1/CAV2 enhancers, which replicate in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2 expression and disrupt MLRs in patient-derived cells, and CRISPR-Cas9 perturbation proximate to a patient mutation is sufficient to reduce CAV1/CAV2 expression in neurons. Additional enrichment of ALS-associated mutations within CAV1 exons positions CAV1 as an ALS risk gene. We propose CAV1/CAV2 overexpression as a personalized medicine target for ALS., Graphical Abstract, Highlights • Identification of ALS-associated genetic variation within gene enhancers • ALS-associated risk variants identified within enhancers and exons linked to CAV1 • CAV1/CAV2 enhancer mutations reduce gene expression and disrupt membrane lipid rafts • CRISPR-Cas9 perturbation of enhancer reduces CAV1/CAV2 expression in neurons, Cooper-Knock et al. identify amyotrophic lateral sclerosis (ALS) risk variants within non-coding regulatory DNA linked to a known ALS gene, TBK1, but also CAV1 and CAV2. Disease-associated variants reduce CAV1/CAV2 expression and disrupt membrane lipid rafts with consequences for neurotrophic signaling. CAV1 coding sequence also contains ALS-associated mutations.