COBLL1 (cordon-bleu WH2 repeat protein like 1) is a protein involved in actin cytoskeleton remodeling and metabolic regulation. Mechanistically, COBLL1 functions through protein-protein interactions; it binds PACSIN2 and competitively inhibits SH3BP1, thereby suppressing the SH3BP1/Rac1 pathway 1. At the cellular level, COBLL1 regulates actin remodeling in differentiating subcutaneous adipocytes, where a causal intronic variant (rs6712203) alters POU2F2 transcription factor binding and COBLL1 expression, impairing lipid accumulation and adipocyte maturation 2. Disease relevance is substantial across multiple conditions. COBLL1 variants are significantly associated with nonalcoholic fatty liver disease (NAFLD) 34, with individuals in the top 1% of genetic risk showing 6-fold increased NAFLD, cirrhosis, and hepatocellular carcinoma risk 3. COBLL1 is also implicated in lipedema, characterized by abnormal subcutaneous adipose tissue deposition 5, and shows sex-dependent interactions with dietary fat intake in obesity risk 6. In hematologic malignancies, elevated COBLL1 expression correlates with tyrosine kinase inhibitor resistance in chr2 myeloid leukemia and predicts worse prognosis 17. COBLL1 expression is also associated with lung cancer survival outcomes 8. Clinically, COBLL1 represents a therapeutic target for metabolic and malignant diseases through modulation of actin dynamics and protein-protein interaction pathways.