VarDCL: A Multimodal PLM-Enhanced Framework for Missense Variant Effect Prediction via Self-distilled Contrastive Learning

Missense variants are a common type of genetic mutation that can alter the structure and function of proteins, thereby affecting the normal physiological processes of organisms. Accurately distinguishing damaging missense variants from benign ones is of great significance for clinical genetic diagnosis, treatment strategy development, and protein engineering. Here, we propose the VarDCL method, which ingeniously integrates multimodal protein language model embeddings and self-distilled contrastive learning to identify subtle sequence and structural differences before and after protein mutations, thereby accurately predicting pathogenic missense variants. First, leveraging sequence and structural information before and after mutations, VarDCL generates sequence-structural multimodal features via different language models. It incorporates both global and local perspectives of feature embeddings to provide the model with dynamic, multimodal, and multi-view input data. Additionally, a Self-distilled Contrastive Learning (SDCL) module was proposed to enable more effective information integration and feature learning, enhancing the models ability to detect sequence and structural changes induced by mutations. Within this module, the multi-level contrastive learning framework excels at capturing information differences before and after mutations within the same modality; meanwhile, the feature self-distillation mechanism effectively utilizes high-level fused features to guide the learning of low-level differential features, facilitating information interaction across different modalities. The VarDCL framework not only ensures the models capacity to learn dynamic changes pre- and post-mutation but also significantly improves cross-modal information interaction between sequence and structure, thereby remarkably boosting the models performance in distinguishing pathogenic mutations from benign ones. To validate the effectiveness of VarDCL, extensive experiments were conducted. The ablation study demonstrates that all key components of VarDCL contribute significantly. On an independent test set containing 18,731 clinical variants, VarDCL achieved an AUC of 0.917, an AUPR of 0.876, an MCC of 0.690, and an F1-score of 0.789, outperforming 21 state-of-the-art existing methods. Benchmark analysis shows that VarDCL can be utilized as an accurate and potent tool for predicting missense variant effects.