A complete protein sequence can usually determine a unique conformation; however, the situation is different for shorter subsequences—some of them are able to adopt unique conformations, independent of context; while others assume diverse conformations in different contexts. The conformations of subsequences are determined by the interplay between local and nonlocal interactions. A quantitative measure of such structural conservation or variability will be useful in the understanding of the sequence–structure relationship. In this report, we developed an approach using the support vector machine method to compute the conformational variability directly from sequences, which is referred to as the sequence structural entropy. As a practical application, we studied the relationship between sequence structural entropy and the hydrogen exchange for a set of well-studied proteins. We found that the slowest exchange cores usually comprise amino acids of the lowest sequence structural entropy. Our results indicate that structural conservation is closely related to the local structural stability. This relationship may have interesting implications in the protein folding processes, and may be useful in the study of the sequence–structure relationship. Proteins 2005. © 2005 Wiley-Liss, Inc.