Background: Objectives: The main goal of this study was to functionally characterize 30 CYP2C19 variants in citalopram metabolism, most of which were rare or novel variants identified in the Chinese Han population. Methods: An Results: In this study, compared to the wild-type enzyme (CYP2C19*1), 73% (22/30) of the CYP2C19 variants showed significantly different metabolic activities in citalopram metabolism. Among them, two variants, CYP2C19*29 and L16F, showed significantly increased intrinsic clearance (nearly 5-fold and 1.5-fold, respectively). Eighteen variants-CYP2C19*2C, *2F, *2G, *2J, *6, *18, *30, *31, *32, *33, N231T, R124Q, R261W, I327T, A430V, R125G, M255T, and I331V-exhibited significantly decreased intrinsic clearance (18.02-63.16%). Two variants, CYP2C19*3 and 35FS, demonstrated weak or no activity. Moreover, the remaining 27% (8/30) of the CYP2C19 variants showed similar metabolic activities to that of the wild-type enzyme. Conclusion: These CYP2C19 variants require specific attention from physicians and researchers, as their altered metabolic activities may influence the safety and efficacy of citalopram treatment. This work greatly expands the previously underexplored knowledge about the metabolic activities of rare or novel CYP2C19 variants in relation to citalopram medication. These findings may further facilitate the precision use of citalopram in personalized medicine.