PMMVar: Leveraging Multi-level Protein Structures for Enhanced Coding Variant Pathogenicity Prediction

Genomic variants, which can disrupt cellular functions, present a challenge in distinguishing deleterious from benign instances. While assessing genome-wide functional impacts, many current algorithms neglect protein tertiary structure of coding region variants due to limitations in protein structural prediction. This study introduces PMMVar, an advanced multimodal deep convolutional network, which adeptly integrates protein tertiary structures with conservation properties from ESM-2, supplemented by other protein structural sequences. PMMVar achieves outstanding performance on the latest clinical variant datasets, NCBI ClinVar (2023), and the Mendelian variant dataset, surpassing existing benchmarks. Ablation analyses validate the significance of protein multi-level structures in enhancing the model's accuracy. Overall, our findings spotlight the essential role of multi-level protein structures in pathogenicity predictions and their potential to discern deleterious genomic variants effectively.