Dissecting genetic variation of local breeds is important for the success of conservation. In this research, we investigated the genomic variation of Colombian Creole (CR) pigs, with a focus on the breed-specific variants in the exonic region of 34 genes with reported effects on adaptive and economic traits. Seven individuals of each of the three CR breeds (CM, Casco de Mula; SP, San Pedreño; and ZU, Zungo) were whole-genome sequenced along with 7 Iberian (IB) pigs and 7 pigs of each of the four most used cosmopolitan (CP) breeds (Duroc, Landrace × Large White, and Pietrain). Molecular variability in CR (6,451,218 variants; from 3,919,242, in SP, to 4,648,069, in CM) was comparable to that in CP, but higher than in IB. For the investigated genes, SP pigs displayed less exonic variants (178) than ZU (254), CM (263), IB (200), and the individual CP genetic types (201 to 335). Sequence variation in these genes confirmed the resemblance of CR to IB and indicates that CR pigs, particularly ZU and CM, are not exempt from selective introgression of other breeds. A total of 50 exonic variants were identified as being potentially specific to CR, including a high-impact deletion in the intron between exons 15 and 16 of the leptin receptor gene, which was only found in CM and ZU. The identification of breed-specific variants in genes related to adaptive and economical traits can bolster the understanding of the role of gene-environment interactions on local adaptation and points the way for effective breeding and conservation of CR pigs.