Background: Core promoter controls transcription initiation. However, little is known for core promoter diversity in the human genome and its relationship with diseases. We hypothesized that as a functional important component in the genome, the core promoter in the human genome could be under evolutionary selection, as reflected by its highly diversification in order to adjust gene expression for better adaptation to the different environment. Results: Applying the “Exome-based Variant Detection in Core-promoters” method, we analyzed human core-promoter diversity by using the 2682 exome data sets of 25 worldwide human populations sequenced by the 1000 Genome Project. Collectively, we identified 31,996 variants in the core promoter region (− 100 to + 100) of 12,509 human genes (https://dbhcpd.fhs.um.edu.mo). Analyzing the rich variation data identified highly ethnic-specific patterns of core promoter variation between different ethnic populations, the genes with highly variable core promoters, the motifs affected by the variants, and their involved functional pathways. eQTL test revealed that 12% of core promoter variants can significantly alter gene expression level. Comparison with GWAS data we located 163 variants as the GWAS identified traits associated with multiple diseases, half of these variants can alter gene expression. Conclusion: Data from our study reals the highly diversified nature of core promoter in the human genome, and highlights that core promoter variation could play important roles not only in gene expression regulation but also in disease predisposition.