BACKGROUND: Chronic gastritis caused by Helicobacter pylori (H. pylori) infection can progress to gastric cancer through atrophic gastritis (AG). The risk of gastric cancer increases with the progression of AG. Therefore, investigating the risk factors for the progression of AG is important. METHODS: Using the GTEx and GEO databases, we extracted thirty-four candidate genes involved in the progression of AG. Then, with in silico analysis using HaploReg v4.1 and JASPAR (Matrix ID: MA0113.3), we extracted rs1231760 of RGS2 as a key single-nucleotide polymorphism (SNP) that could be involved in the functional change in the candidate gene. A correlation analysis between the selected SNP and AG in 200 H. pylori-positive and 302 H. pylori-negative participants was conducted. For functional analysis of the SNP, a dual-luciferase assay using reporter plasmids with a major or minor allele sequence was carried out. RESULTS: The frequency of the C/C genotype of rs1231760 was higher in the AG group than in the non-AG group (p = 0.0471). Functional analysis showed that the transcriptional activities were higher at the dexamethasone-stimulating C allele than at the others (p < 0.05). CONCLUSIONS: The C/C genotype of rs1231760 in RGS2 could be a biomarker of high-risk H. pylori-positive AG because of an increase in RGS2 expression.