Mutation databases can be viewed as footprints of functional organization of a gene and thus can be used to infer its functional organization. We studied the association of exonic splicing enhancers (ESEs) with missense mutations in the tumor suppressor gene TP53 using the International Agency for Research on Cancer (IARC) mutation database. The goals of the study were: (i) to verify the hypothesis that deleterious missense mutations are colocalized with ESEs; (ii) to identify potentially functional ESE sites in the open reading frame (ORF) of the TP53. If some sequence functions as a splicing enhancer, then nucleotide substitutions in the site will disturb splicing, abrogate p53 function, and cause an increased susceptibility to cancer. Therefore, among cancers showing p53 mutations, more missense mutations are expected within functional ESE sites as compared to non-functional ESE motifs. Using several statistical tests, we found that missense mutations in TP53 are strongly colocalized with ESEs, and that only a small fraction of ESE sites contributes to the association. There are usually one or two ESEs per exon showing a statistically significant association with missense mutations--so-called significant ESE sites. In many respects significant ESE sites are different from those that do not show association with missense mutations. We found that positions of significant ESE sites are codon-dependent--significant ESEs preferentially start from the first position of a codon, whereas non-significant ESEs show no position dependence. Significant ESEs showed a more limited set of sequences compared to non-significant ESEs. These findings suggest that there is a limited number of missense mutations that influence ESE sites and our analysis provides further insight into the types of sites that harbor exonic enhancer elements.