SRP409955 PRJNA905683 Genomic diversity of SARS-CoV-2 in Egypt during the third and fourth waves of the pandemic The overall pattern of the SARS-CoV-2 pandemic so far has been a series of waves; surges in new cases followed by declines. The appearance of novel mutations and variants underlie the rises in infections, making surveillance of SARS-CoV-2 mutations and prediction of variant evolution of utmost importance. In this study, we sequenced 320 SARS-CoV-2 viral genomes isolated from patients from the outpatient COVID-19 clinic in the Children Cancer Hospital Egypt 57357 (CCHE 57357) and the Egypt Center for Research and Regenerative Medicine (ECCRM). The samples were collected between March and December 2021, covering the third and fourth waves of the pandemic. The third wave was found to be dominated by Nextclade 20D, with a small number of alpha variant mutations in our samples, despite its spread worldwide. The delta variant was found to dominate the fourth wave in our samples, with the appearance of omicron variants late in 2021. Phylogenetic analysis reveals that the omicron variants are closest genetically to early pandemic variants. Mutation analysis show SNPs, stop codon mutation gain and deletion/insertion mutations, with distinct patterns of mutations governed by Nextclade or WHO variant. While large number of mutations were found in different domains of the spike protein, especially in the omicron variants, the S2 region remains highly conserved throughout all variants. Finally, we observed a large number of highly correlated mutations, and some negatively correlated mutations, and identified a general inclination towards mutations that lead to enhanced thermodynamic stability of the spike protein. Overall, this study contributes genetic and phylogenetic data, as well as provides insights into SARS-CoV-2 viral evolution that may eventually help in the prediction of evolving mutations.