PreMode predicts mode-of-action of missense variants by deep graph representation learning of protein sequence and structural context

Guojie Zhong, Yige Zhao, Demi Zhuang, Wendy K. Chung and Yufeng Shen ()
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Guojie Zhong: Columbia University Irving Medical Center
Yige Zhao: Columbia University Irving Medical Center
Demi Zhuang: Columbia University Irving Medical Center
Wendy K. Chung: Boston Children’s Hospital and Harvard Medical School
Yufeng Shen: Columbia University Irving Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Accurate prediction of the functional impact of missense variants is important for disease gene discovery, clinical genetic diagnostics, therapeutic strategies, and protein engineering. Previous efforts have focused on predicting a binary pathogenicity classification, but the functional impact of missense variants is multi-dimensional. Pathogenic missense variants in the same gene may act through different modes of action (i.e., gain/loss-of-function) by affecting different aspects of protein function. They may result in distinct clinical conditions that require different treatments. We develop a new method, PreMode, to perform gene-specific mode-of-action predictions. PreMode models effects of coding sequence variants using SE(3)-equivariant graph neural networks on protein sequences and structures. Using the largest-to-date set of missense variants with known modes of action, we show that PreMode reaches state-of-the-art performance in multiple types of mode-of-action predictions by efficient transfer-learning. Additionally, PreMode’s prediction of G/LoF variants in a kinase is consistent with inactive-active conformation transition energy changes. Finally, we show that PreMode enables efficient study design of deep mutational scans and can be expanded to fitness optimization of non-human proteins with active learning.

Date: 2025
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DOI: 10.1038/s41467-025-62318-4

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