In this study, we asked whether the AGY serine codon bias and abundance in CDRs were highly conserved from an evolutionary perspective, and if so, whether this might be explained by a selection pressure to enhance overall CDR mutability. We found these features to be conserved in the most primitive vertebrates with an acquired immune system, but not solely because they enhance CDR mutability. Notably, the AGY triplet was abundant only in the Ser reading frame. In an unexpected twist, we found that AGY codons in antiviral antibodies were frequently mutated to codons specifying most of the amino acids that were reported to be key binding-site contact residues for antigen (Ag), as determined from more than 100 crystal structures of Ag–Ab complexes (19). Because the germline codons that gave rise to somatically generated contact residues were not determined in this study, we conducted additional analyses of published Ab–Ag crystal structures to identify germline codons that mutated to codons specifying contact residues. Our independent analyses revealed that somatic mutations in AGY codons created Ag-contact residues more often than mutations in any other synonymous codon group. As such, it appears that AGY CDR codons were preserved because of their exceptional functional plasticity in the context of SHM and affinity maturation.