Our previous study has shown that ATP action on P2X7R could be the second signal to induce the onset of gouty arthritis. However, the function changes of SNPs in the P2X7R, which affect the ATP-P2X7R-IL-1β signaling pathway with high uric acid, remained unknown. We aimed to explore the association between the functional change of the P2X7R containing the Ala348 to Thr polymorphism (rs1718119) and the pathogenesis of gout in the human P2X7 gene (P2RX7). First, 270 gout patients and 70 hyperuricemic patients without a history of gout attack within 5 years were recruited in this study. In addition, in functional studies, changes in ATP-induced pore formation were assessed in HEK-293T cells overexpressing different mutants in P2RX7, the effect on P2X7R-NLRP3-IL-1β pathway activation was explored in THP-1 cells overexpressing them. The gout-sensitivity allele at rs1718119 was A. The AA and AG genotypes exhibited a higher risk of gout. Furthermore, Ala348 to Thr increased P2X7-dependent ethidium+ bromide uptake. More importantly, Ala348 to Thr significantly upregulated the IL-1β and NLRP3 levels compared to the wild type. We suggest that genetic variability in the P2X7R containing the Ala348 to Thr polymorphism may be confers a gain-of-function effect with susceptibility to the development of gout.