Interaction (nonadditive effects) between genetic variants has been highlighted as an important mechanism underlying phenotypic variation, but the discovery of genetic interactions in humans has proved difficult. In this study, we show that the spectrum of variation in the human genome has been shaped by modifier effects of cis-regulatory variation on the functional impact of putatively deleterious protein-coding variants. We analyzed 1000 Genomes population-scale resequencing data from Europe (CEU [Utah residents with Northern and Western European ancestry from the CEPH collection]) and Africa (YRI [Yoruba in Ibadan, Nigeria]) together with gene expression data from arrays and RNA sequencing for the same samples. We observed an underrepresentation of derived putatively functional coding variation on the more highly expressed regulatory haplotype, which suggests stronger purifying selection against deleterious coding variants that have increased penetrance because of their regulatory background. Furthermore, the frequency spectrum and impact size distribution of common regulatory polymorphisms (eQTLs) appear to be shaped in order to minimize the selective disadvantage of having deleterious coding mutations on the more highly expressed haplotype. Interestingly, eQTLs explaining common disease GWAS signals showed an enrichment of putative epistatic effects, suggesting that some disease associations might arise from interactions increasing the penetrance of rare coding variants. In conclusion, our results indicate that regulatory and coding variants often modify the functional impact of each other. This specific type of genetic interaction is detectable from sequencing data in a genome-wide manner, and characterizing these joint effects might help us understand functional mechanisms behind genetic associations to human phenotypes-including both Mendelian and common disease.