Pathogenic missense protein variants affect different functional pathways and proteomic features than healthy...

Area of Science:

• Genetics
• Bioinformatics
• Molecular Biology

Background:

• Missense variants are common in healthy individuals but can cause disease, making classification difficult.
• Understanding variant impact requires insight into molecular principles and affected cellular processes.

Purpose of the Study:

• To develop a statistical framework for quantifying missense variant enrichment across protein structures.
• To identify molecular features distinguishing pathogenic from population variants.

Main Methods:

• Formalized a statistical framework for probabilistic quantification of variant enrichment in proteins, domains, and 3D regions.
• Analyzed variant enrichment in association with functional pathways, transcriptomic, and proteomic data.
• Validated findings against in silico variant impact annotations.

Main Results:

• Pathogenic variants are enriched in proteins involved in cell proliferation and nucleotide processing, and in more abundant proteins.
• Rare population variants share features closer to common variants than pathogenic ones.
• Confirmed trends of variant enrichment in protein surface, core, and interface regions.

Conclusions:

• The study provides molecular insights into protein resilience and sensitivity to missense variants.
• Identified features to prioritize variant-enriched proteins and domains for therapeutic targeting.
• Introduced the ZoomVar database for variant annotation and enrichment analysis.