CRY2 is one of the four central proteins of the cell-autonomous molecular clock in mammals. Numerous missense SNPs have been reported in the cry2 gene which results in missense variants of CRY2. These were correlated with diverse metabolic diseases as well as autism spectrum disorders. Thus, we performed in silico analysis of the human CRY2 (hCRY2) protein, assessing the structural stability and interaction of the protein with the FBXL3 and PER2. Multiple computational tools were used in each phase of the analysis assuring the reliability of the data. The computational study suggests that among 436 missense variants of hCRY2, variants: L74P, L274P, L309P, F315V and Y485H were the most destabilizing missense mutants. These variants were found to alter hCRY2 structure and FAD binding pocket that likely affects the binding of its cofactor FAD and interfering the binding mode of other CRY activating compounds. Structural alterations also reduce the binding affinity to regulatory proteins FBXL3 and PER2, which may cause imbalance in the circadian period length in cells as well as develop multiple abnormalities. These five missense variants warrant detailed in vitro and in vivo investigations to solidify their roles in damaging the protein structure, stability, interaction with protein partners.