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Background: Selective pressure drives SARS-CoV-2 evolution, with spike RBD substitutions shaping ACE2 binding and antibody escape. N481K RBD mutation emerged early in Qatar (2020) and later re-emerged globally, reaching near-fixation by 2024–2025, yet its functional significance remained unexplored. Methods: We analyzed the temporal and geographic circulation of N481K across > 17 million SARS-CoV-2 genomes (2020–2025). Structu...