A major hurdle in understanding the immune pathogenesis of human autoimmune diseases is distinguishing self-reactive “rogue” lymphocytes from normal immune cells required for host defence. The environmental trigger (gluten) and major autoantigen (transglutaminase 2) of Celiac disease are well characterised, but the underlying mechanisms by which rogue lymphocytes cause Celiac disease are unknown. Here, we apply multi-omic technologies that enable detailed DNA, RNA and protein measurements at the single-cell level to profile tens of thousands of immune cells isolated from small intestine duodenum biopsies from individuals with Celiac disease. We utilise the T-cell receptor as a natural barcode across multiple single-cell experiments to identify expanded rogue T cell clones and their gene and cell-surface protein expression profiles, along with any somatic DNA driver mutations. Strikingly, we identify in multiple patients expanded T cell clones with mRNA and cell-surface protein expression profiles of cytotoxic effector cells, that harboured missense somatic mutations in T cell lymphoma driver genes STAT3, STAT5B and DDX3X. These mutations have been described as strong gain-of-function mutations in multiple T cell lymphomas, highlighting a novel mechanism by which T cell clones escape immune tolerance and adopt a rogue phenotype in Celiac disease. Overall, our results highlight the power of single-cell multi-omics in identifying and characterising rare pathogenic clones in a common human autoimmune disease.