The human kinase gene family is composed of 518 genes that are involved in a diverse spectrum of physiological functions. They are also implicated in a number of diseases and encompass 10% of current drug targets. Contemporary, high-throughput sequencing efforts have identified a rich source of naturally occurring single nucleotide polymorphisms (SNPs) in kinases, a subset of which occur in the coding region of genes (cSNPs) and result in a change in the encoded amino acid sequence (nonsynonymous coding SNP; nscSNPs). What fraction of this naturally occurring variation underlies human disease is largely unknown (uDC), and much of it is assumed not to be disease causing (DC). We pursued a comprehensive computational analysis of the distribution of 1463 nscSNPs and 999 DC nscSNPs within the kinase gene family and have found that DCs are overrepresentated in the kinase catalytic domain and in receptor structures. In addition, the frequencies with which specific amino acid changes occur differ between the DCs and the uDCs, implying different biological characteristics for the two sets of human polymorphisms. Our results provide insights into the sequence and structural phenomena associated with naturally occurring kinase nscSNPs that contribute to human diseases.