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Most of our genome comprises noncoding sequences that include diverse transcriptional regulatory elements, such as enhancers, while only ~1.5% of the genome codes for proteins. Nevertheless, DNA sequences that code for protein (exons) can also function as enhancers (eExons) that regulate transcription. Mutations in eExons can lead to multiple phenotypes due to their dual function. The prevalence of protein-coding sequences that possess transcriptional regulatory function (such as eExons) and the consequences of their mutations are not well described. Using advanced sequencing technologies, protein-coding sequences were analyzed for their potential regulatory function in mammalian cells and found to be overrepresented in the genome (>6%). Dissection of the enhancer activity of eExons at single nucleotide resolution in liver cells has demonstrated that: (1) most nucleotide changes with high impact effect are deleterious; (2) deleterious enhancer mutations are correlated with the location of transcription factor-binding sites; (3) synonymous and non-synonymous mutations have similar effects on enhancer activity; and (4) the transcription factor repertoire that controls the activity of enhancers differs across cell types, indicating differences in deleterious mutation profiles. Thus, eExon mutations can disrupt both protein structure and enhancer activity with differential effect across cell types, suggesting that a mutation in a gene could cause a phenotype that has nothing to do with its protein-coding function but is due to its additional hidden regulatory function.