*2.4. Disease-Associated Missense Mutation Distribution in the Sequence of RTT and RTT-like Causing Proteins*

Plotting missense mutations associated with diseases may yield crucial information on structure–function relationships and the features of the protein. We investigated missense mutations in human MeCP2, CDKL5, and FOXG1 that were previously associated with pathogenic RTT from RettBASE and examined the features of the associated sequences. There were 7, 12, and 18 individual amino acid sites in FOXG1, CDKL5, and MeCP2, respectively, that harbored pathogenic missense mutations associated or previously suggested to be associated with pathogenic RTT (Figure 2 and Supplementary Table S4). When the frequencies were combined with those of cases observed for each mutation, MeCP2 had a higher number of cases (1225) than CDKL5 (30) and FOXG1 (8) (Supplementary Tables S4 and S9). Pathogenic RTT or RTT-like-associated missense mutations were more frequently detected in domain regions for all proteins, and in ordered and slowly evolving regions for MeCP2 and CDKL5 (Supplementary Table S9). On the other hand, many mutation sites in MeCP2 were located close to (or in the case of Ser346Arg and Ser134Cys, overlapped with) phosphorylation sites (Figure 2), although the frequency of cases harboring these mutation sites was low (only one for each).
