A rapid solubility assay of protein domain misfolding for pathogenicity assessment of rare DNA sequence variants.

Purpose: DNA sequencing technology has unmasked a vast number of uncharacterized single-nucleotide variants in disease-associated genes, and efficient methods are needed to determine pathogenicity and enable clinical care.

Methods: We report an E. coli-based solubility assay for assessing the effects of variants on protein domain stability for three disease-associated proteins.