by Wenran Li, Shijia Yu, Yingyu Cheng, Sijia WangDNA methylation is a key epigenetic modification that regulates gene expression and plays a vital role in cell differentiation, development, and tumorigenesis. However, large-scale experimental profiling of genome-wide DNA methylation remains time-consuming and limited in coverage. We present DeepMethylation, a deep learning framework that integrates DNA sequence and tissue-specific epigenomic features to predict CpG methylation status across the genome. DeepMethylation achieves state-of-the-art performance (average AUROC 0.909) across tissues, accurately imputes methylation beyond array-covered sites, and enables robust extension from 450k to EPIC array coverage. Feature importance analysis revealed consistent patterns of epigenomic feature contributions across tissues. We also introduced Delta DeepMethylation (DDM), a variant evaluation model to estimate the epigenetic effects of SNPs on DNA methylation. DDM-predicted variant effects were consistent with methylation quantitative trait loci (mQTLs) and not confounded by linkage disequilibrium (LD). Our framework provides a powerful tool for genome-wide methylation prediction and regulatory variant interpretation across tissues.