We identify an ABC regulatory variant rs4810856 that acts as an allele-specific enhancer to distally provoke the expression of PREX1, CSE1L and STAU1 by ZEB1 mediating long-range chromatin interaction loops, which synergistically activate p-AKT signaling and facilitate CRC cells proliferation in vitro and in vivo, thus contributing to an increased risk of CRC (Odds Ratio (OR) = 1.11, 95%CI = 1.05–1.16, P = 4.02 × 10−5). The gene discussed is AKT1; the disease is colorectal carcinoma.