Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first detected in Egypt in February 2020. Data about the prevalence rates of the SARS-CoV-2 lineages are relatively scarce. To understand the genetic characteristics of SARS-CoV-2 in Egypt during several waves of the pandemic, we analyzed sequences of 1256 Egyptian SARS-CoV-2 full genomes from March 2020 to May 2021. From one wave to the next, dominant strains have been observed to be replaced by other dominant strains. We detected an emerging lineage of SARS-CoV-2 in Egypt that shares mutations with the variant of concern (VOC). The neutralizing capacity of sera collected from cases infected with C.36.3 against dominant strains detected in Egypt showed a higher cross reactivity of sera with C.36.3 compared to other strains. Using in silico tools, mutations in the spike of SARS-CoV-2 induced a difference in binding affinity to the viral receptor. The C.36 lineage is the most dominant SARS-CoV-2 lineage in Egypt, and the heterotrophic antigenicity of SARS-CoV-2 variants is asymmetric. These results highlight the value of genetic and antigenic analyses of circulating strains in regions where published sequences are limited.