The prevalence of protein misfolding as a mechanism for hereditary deafness.

Incorporating protein folding stability into Bayesian models predicts 28,866 VUSs as likely pathogenic in hereditary deafness, with 12,424 showing severe destabilization.

• Why it matters: Understanding the role of protein misfolding in hereditary deafness addresses a key gap in classifying uncertain variants and improves diagnostic accuracy for affected individuals.
• What they did: The study evaluated 381,924 missense variants across 224 genes using probabilistic frameworks, comparing models based on ACMG/AMP guidelines, and integrated protein folding stability into Bayesian predictions.
• The result: The protein-folding informed model prioritized variants with high pathogenic probability, leading to the reclassification of twelve probands' genetic diagnoses and highlighting the importance of biophysical analysis in variant interpretation.