The bacteria Helicobacter pylori activates the cellular degradation mechanism known as Autophagy. The autophagy gene ATG16L1 (rs2241880, G-allele) has a single nucleotide polymorphism (SNP) that has been linked to dysregulation of autophagy and enhanced ER stress. Researchers went further by examining the effects of this SNP in H. pylori-mediated gastric cancer development, as well as its molecular pathways. ATG16L1 rs2241880 was studied in individuals from diverse ethnic groups (Dutch and Australian) with a range of gastric (pre)malignant severity. GRP78 (a biomarker for ER stress) was measured in gastric tissues. In organoids and CRISPR/Cas9 modified cell lines, the impact of ATG16L1 rs2241880 on H. pylori-mediated ER stress and pro-inflammatory cytokine production was investigated. The ATG16L1 rs2241880 G-allele was linked to an increased incidence of gastric cancer. Increased amounts of ER stress were found in intestinal metaplastic cells in gastric tissue of patients. H. pylori upregulates autophagy while reducing ER stress in vitro models, which was suggested to be partly caused by the ATG16L1 rs2241880 genotype. In cells homozygous for the G-allele, H. pylori-induced IL-8 production was raised and TNF-α production was lowered. The ATG16L1 rs2241880 G-allele is linked to stomach premalignant diseases and cancer progression. Underlying this increased risk is the ability of ATG16L1 rs2441880 to regulate H. pylori-induced ER stress pathways and pro-inflammatory mediators.