CLCC1 is an anion-selective chloride channel localized to the endoplasmic reticulum (ER) membrane that functions as a critical regulator of cellular homeostasis through multiple interconnected mechanisms. Primary function: CLCC1 mediates chloride efflux from the ER lumen in a calcium-dependent, voltage-independent manner, compensating for positive charge loss during calcium release and maintaining ER calcium pools 1. This activity supports unfolded protein response (UPR) activation to prevent misfolded protein accumulation 12. Mechanism: CLCC1 operates at ER-mitochondria contact sites where it interacts with the mitochondrial microprotein PIGBOS to coordinate inter-organelle communication 1. The protein contains a domain homologous to yeast nuclear pore assembly factors, suggesting roles in membrane remodeling beyond ion transport 3. CLCC1 also promotes nuclear envelope fusion during herpesvirus egress and host nuclear morphogenesis 45, and regulates hepatic neutral lipid trafficking 3. Disease relevance: Rare heterozygous CLCC1 variants are associated with amyotrophic lateral sclerosis (ALS), with affected patients showing early-onset, rapid progression with spinal onset and cognitive involvement 67. CLCC1 dysfunction also links to retinitis pigmentosa and cholestatic liver disease pathogenesis 8. Additionally, SARS-CoV-2 ORF3A protein targets CLCC1 to dysregulate UPR during viral infection 2. Clinical significance: CLCC1 emerges as a pleiotrophic regulator with therapeutic potential in neurodegenerative diseases and viral infections through modulation of ER calcium signaling and protein quality control.