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Membrane proteins are unique in that segments thereof concurrently reside in vastly different physicochemical environments: the extracellular space, the lipid bilayer, and the cytoplasm. Accordingly, the effects of missense variants disrupting their sequence depend greatly on the characteristics of the environment of the protein segment affected as well as the function it performs. Because membrane proteins have many crucial roles (transport, signal transduction, cell adhesion, etc.), compromising their functionality often leads to diseases including cancers, diabetes mellitus or cystic fibrosis. Here, we report a suite of sequence‐based computational methods “Pred‐MutHTP” for discriminating between disease‐causing and neutral alterations in their sequence. With a data set of 11,846 disease‐causing and 9,533 neutral mutations, we obtained an accuracy of 74% and 78% with 10‐fold group‐wise cross‐validation …