Transient excited states in proteins can be accurately probed from temperature dependence of amide proton (H-1(N)) chemical shifts displaying significant curvatures. Characterizing these near-native alternative states is of high therapeutic relevance in conformational diseases wherein missense mutations promote structural instability that leads to conformational heterogeneity. Extending the structure function paradigm from physiology to pathology, we recently reported the solution NMR structure and dynamics of a severe congenital cataract variant, G57W of human gamma S-crystallin (abbreviated as gamma S-G57W) which is resistant towards crystallization. In an endeavour to explore the functional consequences of this mutation, here we report for the first time, native state conformational ruggedness in human gamma S-G57W as compared to its wild-type counterpart from residue resolved nonlinear temperature dependence of backbone H-1(N) chemical shifts using solution NMR spectroscopy. Our calculations suggest that the simulated chemical shift curvatures are indicative of low energy excited states within 2-4 kcal mol(-1) from the native state. Residues accessing alternative conformations populate the N-terminal domain of gamma S-G57W more than its C-terminal counterpart. Collectively, curvatures retaining native state ensemble on mild denaturation suggest that the free energy landscape in human gamma S-G57W at the bottom of the folding funnel is sufficiently robust and malleable against such perturbations. Overall, this critical study highlights the functional aspects of such structural malleability promoting infantile cataracts as a global health risk marker. (C) 2019 Elsevier Inc. All rights reserved.