Wheat (Triticum aestivum L.) is one of the world's most important food crops and its production is frequently threatened by diseases caused by several biotrophic pathogens, including stripe rust, leaf rust, stem rust and powdery mildew. Identifying and cloning genes that confer resistance to multiple-diseases hold significant value for breeding wheat cultivars with broad-spectrum disease resistance. In this study, a wheat autoimmunity-B2 (WAI-B2) gene is cloned from an ethyl methanesulfonate (EMS)-induced wheat autoimmunity mutant, 8P4087, and its role in resistance against multiple foliar diseases is characterized. WAI-B2 encodes a unique transmembrane protein that provides resistance to powdery mildew, stripe rust, leaf rust and stem rust in wheat. Further analysis reveals that WAI-B2 interacts with the TaHsp90 and TaHsp70, which is crucial for cell stabilization, signal transduction and programed cell death (PCD). Used AlphaFold 2 and SWISS-MODEL to predict the optimal amino acid substitution and hydrogen bond interaction sites, a series of new WAI-B2 alleles is designed, and alleles capable of causing mild cell death in N. benthamiana are obtained. This study provides valuable insights into the potential of artificial intelligence (AI)-assisted approaches for designing disease-resistant crops in the future.