Recently, SASH1 has emerged as a novel protein interactor of a few Eph tyrosine kinase receptors like EphA2. These interactions involve the first N-terminal Sam (sterile alpha motif) domain of SASH1 (SASH1-Sam1) and the Sam domain of Eph receptors. Currently, the functional meaning of the SASH1-Sam1/EphA2-Sam complex is unknown, but EphA2 is a well-established and crucial player in cancer onset and progression. Thus, herein, to investigate a possible correlation between the formation of the SASH1-Sam1/EphA2-Sam complex and EphA2 activity in cancer, cancer-linked mutations in SASH1-Sam1 were deeply analyzed. Our research plan relied first on searching the COSMIC database for cancer-related SASH1 variants carrying missense mutations in the Sam1 domain and then, through a variety of bioinformatic tools and molecular dynamic simulations, studying how these mutations could affect the stability of SASH1-Sam1 alone, leading eventually to a defective fold. Next, through docking studies, with the support of AlphaFold2 structure predictions, we investigated if/how mutations in SASH1-Sam1 could affect binding to EphA2-Sam. Our study, apart from presenting a solid multistep research protocol to analyze structural consequences related to cancer-associated protein variants with the support of cutting-edge artificial intelligence tools, suggests a few mutations that could more likely modulate the interaction between SASH1-Sam1 and EphA2-Sam.