What types of amino acid substitutions are functionally tolerated in an epitope? This question is of importance because the immunogenicity, pathogenicity, and therapeutic potential of a peptide can be determined by a single amino acid change. As an example, a single amino acid change in the encephalitogenic myelin oligodendrocyte glycoprotein WYRSPFSRVV peptide confers the capacity to ameliorate and reverse experimental autoimmune encephalomyelitis. Currently, no rule is available to predict/explain the functional outcomes of amino acid changes. To address this issue, we examined the role of single amino acid changes in immune responses by applying proteomic similarity analyses to available data. We found that the loss or gain of immunological information in a peptide epitope following an amino acid substitution often is related to a gain or loss in the proteomic similarity. Rare, but significant epitopic sequences become immunologically insignificant when an amino acid change makes them common, repeated sequences. This study confirms that low similarity to the host proteome is a major factor in modulating the immune epitope repertoire.