Background: Mutations among the structural proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to the emergence of new variants with different features in mortality and sensitivity toward drugs and vaccines. Here we aimed to investigate the mutations among structural proteins of SARS-CoV-2 globally.Methods: We analyzed samples of amino-acid sequences (AASs) for envelope (E), membrane (M), nucleocapsid (N), and spike (S) proteins from declaration the coronavirus 2019 (COVID-19) as pandemic to January 2022. Then, the existence of mutations and their locations have been considered by the sequence alignment to the reference sequence, categorized based on frequency and continent. Finally, the related human genes with the viral structural genes have been discovered, and their interactions have been reported.Results: The results indicated that the most relative mutations among the E, M, N, and S AASs happened in the regions of 7 to 14, 66 to 88, 164 to 205, and 508 to 635 AAs, respectively. The most frequent mutations in E, M, N, and S proteins were concluded as T9I, I82T, R203M/R203K, and D614G. D614G is the most frequent mutation in all six geographical areas. Following D614G, L18F, A222V, E484K, and N501Y rank second to fifth most frequent mutations in S protein globally. Besides, A-kinase Anchoring Protein 8 Like (AKAP8L) has been shown as the linkage unit between M, E, and E cluster genes.Conclusion: Screening the mutations of structural proteins can help scientists introduce better drug and vaccine development strategies.