Aims/hypothesis: Islet autoantibodies (AAbs) are detected in >90% of individuals with clinically suspected type 1 diabetes (T1D) at onset. A single AAb and sometimes at low titer is often detected in AAb-positive individuals making their diabetes type diagnosis uncertain. T1D genetic risk score (GRS) is a useful tool for discriminating polygenic autoimmune T1D from other types of diabetes and particularly the monogenic forms, but testing is not routinely performed in clinical care. Here, we leveraged the T1D GRS for identifying individuals with clinically suspected T1D although weak evidence of autoimmunity, i.e., individuals with an indication for monogenic diabetes testing. Methods: We studied 63 individuals with diabetes, 45 of whom were AAb-negative and 18 single AAb-positive at disease onset. Seventy-three pediatric individuals with multiple AAbs were included as controls. We calculated the T1D GRS and analyzed by clinical exome sequencing the 45 AAb-negative and 18 single AAb-positive individuals. Results: The T1D GRS was significantly lower in AAb-negative individuals than in those with single and multiple AAbs. Pathogenic variants in maturity-onset diabetes of the young (MODY) or monogenic diabetes genes were identified in 17 (37.8%) AAb-negative individuals. Age and C-peptide levels at diagnosis were higher in individuals with a confirmed diagnosis of MODY/monogenic diabetes compared to those without pathogenic variants. Interestingly, pathogenic variants in MODY genes were found in 2 (11%) single AAb-positive individuals. Single AAb-positive patients with MODY mutations had a lower T1D GRS compared to non-MODY patients. Conclusions: These findings provide insights into the genetic makeup of patients with no AAbs or single AAb at disease onset. The absence of AAbs or the presence of a single AAb is indicative of a monogenic form of diabetes especially when associated with a low T1D GRS.