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Simple Summary: This study explores the structural and stability impacts of rare genetic and somatic mutations in two glutathione peroxidase proteins, GPx7 and GPx8, which play crucial roles in cellular stress responses. This study aims to identify how these mutations affect protein stability, as these changes are often associated with cancers and other complex diseases. Using advanced computational methods, this research analyzed thousands of potential mutations to predict their effects on protein function. The findings reveal that destabilizing mutations are more likely to be associated with diseases, providing insights into the molecular mechanisms of cancer development. By focusing on high-impact mutations, this study provides a foundation for developing targeted therapies and better understanding the molecular basis of diseases associated with these proteins. Background/Objectives: Somatic and genetic mutations in glutathione peroxidases (GPxs), including GPx7 and GPx8, have been linked to intellectual disability, microcephaly, and various tumors. GPx7 and GPx8 evolved the latest among the GPx enzymes and are present in the endoplasmic reticulum. Although lacking a glutathione binding domain, GPx7 and GPx8 possess peroxidase activity that helps the body respond to cellular stress. However, the protein mutations in these peroxidases remain relatively understudied. Methods: By elucidating the structural and stability consequences of missense mutations, this study aims to provide insights into the pathogenic mechanisms involved in different cancers, thereby aiding clinical diagnosis, treatment strategies, and the development of targeted therapies. We performed saturated computational mutagenesis to analyze 2926 and 3971 missense mutations of GPx7 and GPx8, respectively. Results: The results indicate that G153H and G153F in GPx7 are highly destabilizing, while E93M and W142F are stabilizing. In GPx8, N74W and G173W caused the most instability while S70I and S119P increased stability. Our analysis shows that highly destabilizing somatic and genetic mutations are more likely pathogenic compared to stabilizing mutations. Conclusions: This comprehensive analysis of missense mutations in GPx7 and GPx8 provides critical insights into their impact on protein structure and stability, contributing to a deeper understanding of the roles of somatic mutations in cancer development and progression. These findings can inform more precise clinical diagnostics and targeted treatment approaches for cancers. [ABSTRACT FROM AUTHOR]