March 31, 2026
Interpreting somatic mutations in cancer genes remains a major challenge in clinical genomics. While large-scale tumor sequencing efforts have identified hundreds of recurrently mutated genes, the functional consequences of many individual mutations remain unclear, limiting their use in clinical decision-making.
To address this gap, researchers have developed a new proteo-genomics framework that integrates mutations with 3D protein structures predicted by AlphaFold. Using genomics data from almost 140,000 tumors, the framework identifies regions where mutations accumulate beyond what would be expected by random chance and maps these regions onto protein structures and their relation to functional domains, protein-ligand interaction interfaces, post-translational modification sites, and other structural features.
The framework is available through an interactive web resource, OncoFold. With OncoFold, users can interactively select their gene of interest, visualize different types of mutations with or without ligands in the context of their protein structure, and integrate contextual information related to secondary structures, protein domains, protein stability, solvent accessibility, and other mechanisms for interpreting mutations and associated mechanisms. The website further offers an interactive download feature, allowing users to export the functional predictions from the model as a table and integrate it for follow-up interpretation workflows.
Broadly, by linking somatic mutations to tumorigenic mechanisms through protein structure, this resource provides a scalable and unbiased approach to variant interpretation at single-base resolution. It helps researchers with phenotype-based assessment and may support future efforts in variant interpretation, patient stratification, and clinical response prediction.
If you are interested in learning more about OncoFold, do not miss the Webinar on April 09 at 11 AM, which will cover everything you need to know about OncoFold. If you need additional help, the OncoFold team welcomes questions (see contact details on the website).
– Do Young Hyeon, Yuxiang Zhou, and Felix Dietlein (OncoFold Team)
This topic spotlight was authored on March 31, 2026 and reflects the information available at that time. As content may evolve, please contact us at ncibtep@nih.gov to obtain the most current information.