Mutations in several phosphorylation sites within the phosphorylation rich domain of SARS-COV-2 Nucleocapsid protein (NCp), including serines 186, 197 and 202, and adjacent arginine 203 and glycine 204 have been described and have been proposed to prevent the binding and sequestration of NCp by Protein 14-3-3. Structure modeling and thermodynamic calculation show that mutations of phosphorylation sites, phospho-serines 186, 197 and 202 to phenylalanine, leucine and asparagine, and phosphorylation recognition sites, arginine/glycine 203/204 to lysine/arginine or lysine/threonine resulted in signifi cant destabilization of the NCp-14-3-3 complex by causing a decrease in Stability Energy (ΔGstability energy) and Binding Energy (ΔΔGbinding energy). These results evidenced that mutations in NCp underlie a mechanism to bypass sequestration by Protein 14-3-3 which would result in enhanced dimerization of NCp, and replication, transcription and packaging of the SARS-COV-2 genome