AbstractA deeper understanding of genetic regulation and functional mechanisms underlying genetic associations with complex traits and diseases is impeded by cellular heterogeneity and linkage disequilibrium. To address these limits, we introduce Huatuo, a framework to decode genetic variation of gene regulation at cell type and single-nucleotide resolutions by integrating deep-learning-based variant predictions with population-based association analyses. We apply Huatuo to generate a comprehensive cell type-specific genetic variation landscape across human tissues and further evaluate their potential roles in complex diseases and traits. Finally, we show that Huatuo’s inferences permit prioritizations of driver cell types associated with complex traits and diseases and allow for systematic insights into the mechanisms of phenotype-causal genetic variation.