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Using the SARS-CoV-2 receptor-binding domain as a model, this study combines large-scale antibody sequencing, deep mutational scanning, and AlphaFold 3 structural modeling to investigate the basis of immunodominant epitope selection. The results show that germline-encoded antibody features are a primary driver of immunodominance. Specifically, 76% of RBD-targeting antibodies display conserved gene segment usage and\/or germline-encoded HCDR3 motifs. Structural analyses identified recurrent germline-encoded residues within these regions that interact with immunodominant epitopes, and mutating these residues eliminated binding. Mutations in SARS-CoV-2 variants frequently disrupt these interactions and are associated with immune escape; other mutations enable germline-mediated recognition and generate new immunodominant epitopes. 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