Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organise membrane lipid rafts (MLR) important for cell signalling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localise a large proportion of ALS-risk variants within the non-coding genome, but further characterisation has been limited by lack of appropriate tools. Applying a new pipeline to identify pathogenic genetic variation within enhancer-elements responsible for regulating gene expression, we have discovered disease-associated variation within CAV1/CAV2 enhancers, which replicated in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2 expression and disrupt MLR 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 a new ALS gene. We propose CAV1/CAV2 overexpression as a personalised medicine target for ALS.