Regulation of gene expression has recently been complexified by the identification of Epromoters, a subset of promoters with enhancer function. Here, we uncovered the first dual cis-regulatory element, "ESpromoter," exhibiting both enhancer and silencer function, as a regulator of the nearby genes ATP2B4 and LAX1 in single human T cells. Through integrative approach, we pinpointed functional rs11240391, a severe malaria risk variant that escapes detection in genome-wide association studies, challenging conventional strategies for identifying causal variants. CRISPR-modified cells demonstrated the regulatory effect of ESpromoter and rs11240391 on LAX1 expression and T cell activation. Furthermore, our findings revealed an epistatic interaction between ESpromoter SNPs and rs11240391, impacting severe malaria susceptibility by further reducing LAX1 expression. This groundbreaking discovery challenges the conventional enhancer-silencer dichotomy. It highlights the sophistication of transcriptional regulation and argues for an integrated approach combining genetics, epigenetics, and genomics to identify new therapeutic targets for complex diseases. HIGHLIGHTS Novel dual enhancer-silencer element (ESpromoter) in a single human cell type Functional SNP for severe malaria risk that escapes genome-wide association studies Genome editing at the SNP demonstrates a regulatory effect on LAX1 and T cell activation Epistatic interaction between SNPs increases the risk of severe malaria In brief Epistatic interaction between common variants within a novel dual enhancer-silencer regulatory element and the LAX1 promoter variant is responsible for severe malaria susceptibility through T-cell activation.