Our two recent reports on the high resolution NMR structure and conformational dynamics of G57W variant of human gamma S-crystallin (abbreviated as gamma S-G57W) causing severe infantile cataracts, revealed slackening of its N-terminal domain with enhanced local conformational dynamics attributed to mutation. Exploring the biochemistry of infantile cataracts in detail, here we studied structural unfolding in both human gamma S-WT and gamma S-G57W at residue level resolution using solution NMR spectroscopy and chemical kinetics and characterized the molecular intermediates with functional consequences. We report, for the first time, that human gamma S-crystallin unfolds sequentially under H/D exchange. This communication forms the first experimental evidence for non-concerted destabilization of structural foldon units in human gamma S-G57W. Residues contributing to the compact fold and structural stability exchanged their amide protons with deuterons more readily in gamma S-G57W compared to gamma S-WT, displaying differential free energies of exchange. Overall, our results establish a direct conformational link between the structure, dynamics, design and function in human gamma S-crystallin such that the G57W cataract variant promotes enhanced structural excursions concomitant with increased instability, elucidating very crucial molecular details of cataract formation affecting infants across the globe. (C) 2019 Elsevier Inc. All rights reserved.