We link rare CLCC1 mutations to ALS and demonstrate that the ALS-associated mutations impair CLCC1 channel activity, damage ER ion homeostasis, and promote ER stress in the brain, implying that disruption of ER ion homeostasis maintained by CLCC1 underlies the etiology of neurodegenerative disease. The gene discussed is CLCC1; the disease is amyotrophic lateral sclerosis.