Neuronal plasticity is associated with alternative splicing and epigenetic modulation. Recent evidence reveals the association of cytosine methylation with alternative splicing and splicing regulatory mechanisms. Single nucleotide polymorphisms (SNPs) are generally less frequent in conserved coding regions and probably in splice sites, compared to non-coding regions. CpG polymorphisms in coding regions and splice sites and their association with splicing regulatory elements have not been investigated till presently. We currently analyzed the CpG variability in 28 genes (361 constitutive and 105 alternative exons and the corresponding splice sites) associated with neurodegenerative diseases (ND). CpG polymorphisms in the splice sites of these genes are particularly frequent when compared to those at AG sequences. Moreover, in both constitutive and alternative exons, polymorphisms in CpGs are more frequent than in AG, GT sequences. On the contrary, in the polypyrimidine acceptor sequence C/T conservation is prominent indicating that in this locus the sequence of cytosines and thymines is preserved. Bioinformatic analysis of the splicing-associated regulatory elements in these exons and splice sites reveals that 18 out of a total of 39 SNPs which could strongly affect splicing (>1.5 score difference) contain CpG sequences. Cytosines are considerably more frequent and variable than expected at the position preceding the GT splice donors, while sites of epigenetic modification are absent from acceptors. The high CpG frequency in polymorphic splicing-associated sites implicates the involvement of epigenetic mechanisms in splicing selection decisions regulated by these sites, and indicates the complexity of genetic studies involving these, tentatively critical, polymorphisms in ND.