Autoantibodies are responsible for severe autoimmune disease manifestations, including cutaneous vasculitis and glomerulonephritis. However, autoantibodies are also detected in the serum of patients with mild disease and asymptomatic individuals years prior to the development of overt autoimmunity. A major challenge for clinicians is predicting which patients will develop severe and life-threatening pathology. The aim of this work was to isolate the B cells responsible for producing pathogenic autoantibodies and test for molecular changes that may explain the transition from benign to pathogenic autoimmunity. Mass spectrometry sequencing of serum autoantibodies was combined with massively parallel antibody sequencing and single cell DNA/RNA sequencing to identify rare circulating B cells expressing autoantibodies. Using this approach, we identified a cascade of somatic genetic events that converted a benign autoantibody into an autoantibody with increased propensity to form insoluble aggregates capable of initiating inflammation. The ability to detect clones producing pathogenic autoantibodies provides new insights into disease pathogenesis and strategies for precision medicine approaches to selectively target pathogenic B cells.