A graph neural network approach for accurate prediction of pathogenicity in multi-type variants

Abstract Accurate prediction of pathogenic variants in human disease-associated genes would have a profound effect on clinical decision-making; however, it remains a significant challenge due to the overwhelming number of these variants. We propose graph neural network for multimodal annotation-based pathogenicity prediction (GNN-MAP), a novel deep learning framework that effectively integrates multimodal annotations and similarity relationships among variants to predict the pathogenicity of multi-type variants. Trained on the ClinVar dataset, GNN-MAP exhibits superior predictive performance in internal validation and orthogonal test datasets, accurately predicting variant pathogenicity. Notably, GNN-MAP enables accurate prediction of the pathogenicity of rare variants and highly imbalanced datasets. Furthermore, it achieves high performance in the pathogenicity prediction of inherited retinal disease-specific variants, highlighting its effectiveness in disease-specific variant prediction. These findings suggest that the robust capability of GNN-MAP to predict pathogenicity across multiple variant types and datasets holds significant potential for applications in research and clinical settings.