A new SARS-CoV-2 variant, 501Y.V2, was identified in South Africa, characterized by eight mutations in the spike protein, including K417N, E484K, and N501Y, which may affect viral function. This variant emerged in the Nelson Mandela Bay area during the first wave of the epidemic and rapidly spread to three provinces, becoming dominant by the end of 2020. Genomic data suggest this variant has a selective advantage, possibly due to increased transmissibility or immune escape. The variant was detected through intensified genomic surveillance in response to a resurgence of cases in the Eastern Cape. The variant contains multiple mutations in the spike protein, including those in the receptor-binding domain (RBD), which may enhance binding to human ACE2 and contribute to immune escape. Analysis of mutations in the spike protein shows a higher rate of substitution compared to other lineages, indicating increased evolutionary pressure. The variant's mutations may also contribute to increased transmissibility, as evidenced by its rapid spread and displacement of other lineages. The variant's emergence and spread highlight the importance of genomic surveillance in tracking viral evolution and informing public health responses. The study underscores the need for coordinated global efforts to monitor and respond to emerging variants of concern.A new SARS-CoV-2 variant, 501Y.V2, was identified in South Africa, characterized by eight mutations in the spike protein, including K417N, E484K, and N501Y, which may affect viral function. This variant emerged in the Nelson Mandela Bay area during the first wave of the epidemic and rapidly spread to three provinces, becoming dominant by the end of 2020. Genomic data suggest this variant has a selective advantage, possibly due to increased transmissibility or immune escape. The variant was detected through intensified genomic surveillance in response to a resurgence of cases in the Eastern Cape. The variant contains multiple mutations in the spike protein, including those in the receptor-binding domain (RBD), which may enhance binding to human ACE2 and contribute to immune escape. Analysis of mutations in the spike protein shows a higher rate of substitution compared to other lineages, indicating increased evolutionary pressure. The variant's mutations may also contribute to increased transmissibility, as evidenced by its rapid spread and displacement of other lineages. The variant's emergence and spread highlight the importance of genomic surveillance in tracking viral evolution and informing public health responses. The study underscores the need for coordinated global efforts to monitor and respond to emerging variants of concern.