In contrast to monogenic diabetes, the genetic investigations of common forms of type 2 diabetes (T2D) have led to modest advances in precision medicine. We aimed to assess the prevalence in common T2D of pathogenic mutations across 33 genes causing monogenic diabetes, and to compare it to the prevalence found in normoglycemic individuals. Through next-generation sequencing, genes were sequenced in a case-control study including more than 6,000 individuals. We then applied stringent quality control steps before the analyses. The pathogenicity of variants was assessed using the American College of Medical Genetics and Genomics criteria. Primary outcome was the prevalence of pathogenic or likely pathogenic mutations in the case-control study. Secondary outcomes included age of T2D diagnosis, body mass index, T2D treatment and T2D family history. We found a significant association between pathogenic or likely pathogenic variants and T2D risk (p<0.001; 6.5% of carriers among cases). This association was explained in part by pathogenic mutations of two actionable genes, GCK and HNF1A. Overall, among cases, carriers were leaner (β=-1.5±0.5 kg/m²; p<0.01) and tended to develop T2D earlier (β=-1.2±0.7 years; p=0.05) compared to non-carriers, but use of antidiabetic drugs and T2D family history were not different. We reported a high prevalence of pathogenic mutations in monogenic diabetes genes among common T2D patients who did not present with clinical characteristics of monogenic diabetes (i.e., MODY). These results could lead to precision diabetic medicine, and to significant savings in health expenditure via systematic molecular diagnosis of newly diagnosed patients. Disclosure A. Bonnefond: None. P. Froguel: None. Funding European Research Council; French National Research Agency