dehydration propensity of orderdisorder intermediate regions in soluble proteins soluble folded proteins maintain their structural integrity by properly shielding most backbone amides and carbonyls from full hydration this structure wrapping entails a proper packing of the intramolecular hydrogen bonds thus a poorly wrapped hydrogen bond constitutes an identifiable packing defect such defects are promoters of protein associations since they favor the removal of hydrating molecules in this work we show that large clusters of packing defects generate the most significant dehydration hot spots on the protein surface inducing a strong dielectric modulation that is reflected by a local quenching of the dielectric permittivity the pdbreported proteins with the largest clusters of packing defects are found to be three cancerrelated transcription factors four highly interactive proteins related to cell signaling and cytoskeleton and a cellular prion protein a large concentration of packing defects in a soluble protein constitutes a structural singularity that is intermediate between order and disorder the functional implications of this singularity are investigated to delineate diverse interrelated roles the presence of these large clusters signals a structural vulnerability a pronounced dehydration propensity and a strong electrostatic enhancement