Most autoimmune disease-associated variants lie in non-coding regions, but the molecular mechanisms linking these variants to gene regulation remain poorly understood. A major unresolved challenge is to determine how disease alleles alter transcription factor (TF) binding, cofactor (COF) recruitment, and enhancer activity at scale. Here, we applied CASCADE to 2,853 autoimmune disease-associated variants in Jurkat T cells, profiling differential binding of five TFs and ten COFs and identifying 508 binding-modulating variants. Binding changes were enriched among MPRA-defined expression-modulating variants and were strongly concordant with allele-specific reporter expression, linking altered TF/COF recruitment to enhancer activity. Notably, many expression-modulating variants perturbed COF binding alone, highlighting COF recruitment as an informative layer of variant mechanism. CASCADE motif analysis identified major TF families disrupted by autoimmune variants, including ETS, RUNX, SP/KLF, OVOL/MYBL, and bHLH factors. At individual loci, CASCADE revealed allele-dependent TF-family switching and a recurrent ETS-associated regulatory module involving FOXM1 and the cofactors TIP60, BRD4, NCOA3, and SRC1. Together, this integrated biochemical and functional framework prioritizes autoimmune disease-associated variants by linking allele-specific TF/COF binding mechanisms to enhancer activity.