Conserved water molecules shape the pathogenicity of missense variants in human proteins.

Conserved water molecules (CWMs) are linked to missense variant pathogenicity in human proteins, with pathogenic variants significantly enriched at CWM sites.

• Why it matters: CWMs are known to affect stability and ligand binding, but their role in shaping how human missense variants become pathogenic is largely unexplored.
• What they did: The study predicted ligand-binding and CWM sites across human PDB structures and mapped missense variants to these sites and remaining protein surface; it also ran molecular dynamics simulations of GBA1 (GCase) comparing wild-type and the pathogenic L444P variant.
• The result: Pathogenic variants were significantly enriched at CWM sites, exceeding enrichment at binding sites overall, and in simulations destabilizing a CWM in wild-type GCase produced changes resembling L444P, while stabilizing the CWM in L444P shifted measures toward wild-type behavior.

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