Curiously, our analyses of the germline repertoire of IgV-region genes revealed that these seemingly dangerous AGY Ser codons are unusually abundant in sequences specifying CDRs, a phenomenon that is conserved in human and mouse repertoires (1, 2). As such, VH, Vκ, and Vλ genes appear poised to mutate in a manner that would frequently generate antinuclear activity in the specified Ab product. Moreover, AGY Ser codons are more frequent than TCN Ser codons in germline IgV-region CDRs, a bias that does not apply to αβTCRV-region genes, which favor TCN over AGY codons (3, 17, 18). Because AGY, but not TCN, is an intrinsically preferred target of SHM, it was speculated that this AGY bias evolved to enhance targeting of SHM to antibody CDRs (17).