Natural genetic diversity modulates structural stability changes caused by pathogenic variants in small proteins

Clinical genomics relies heavily on linear reference genomes such as GRCh38, often neglecting natural sequence diversity that can modify variant expressivity and drive diagnostic health disparities. Meanwhile, variant interpretation is moving toward direct biophysical evidence of disrupted protein function, yet how natural genetic backgrounds modulate variant-induced protein stability changes remains uncharacterized. Here, we present a physics-based computational and data processing framework to evaluate how global sequence diversity alters the predicted thermodynamic impact of pathogenic muta

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