biostudies-literatureHanna GWellcome TrustBiotechnology and Biological Sciences Research Council168374https://www.ebi.ac.uk/biostudies/studies/S-EPMC7617522biostudies-literatureUnknown436(2)Variant effect predictors assess if a substitution is pathogenic or benign. Most predictors, including those that are structure-based, are designed for globular proteins in aqueous environments and do not consider that the variant residue is located within the membrane. We report Missense3D-TM that provides a structure-based assessment of the impact of a missense variant located within a membrane. On a dataset of 2,078 pathogenic and 1,060 benign variants, spanning 711 proteins from 706 structures, Missense3D-TM achieved an accuracy of 66%, Mathews correlation coefficient of 0.37, sensitivity of 58% and specificity of 81%. Missense3D-TM performed similarly to mCSM-membrane: accuracy 66% vs 61% (p = 0.02) on an unbalanced test set and 70% vs 67% (p = 0.20) on a balanced test set. The Missense3D-TM website provides an analysis of the structural effects of the variant along with its predicted position within the membrane. The web server is available at http://missense3d.bc.ic.ac.uk/.Journal of molecular biologyMissense3D-TM: Predicting the Effect of Missense Variants in Helical Transmembrane Protein Regions Using 3D Protein Structures.PMC7617522BB/T010487/1218242BB/P023959/1BB/X01830X/1218242/Z/19/Z104955104955/Z/14/ZKhanna TIslam SAHanna GDavid ASternberg MJEfalseMissense3D-TM: Predicting the Effect of Missense Variants in Helical Transmembrane Protein Regions Using 3D Protein Structures.Variant effect predictors assess if a substitution is pathogenic or benign. Most predictors, including those that are structure-based, are designed for globular proteins in aqueous environments and do not consider that the variant residue is located within the membrane. We report Missense3D-TM that provides a structure-based assessment of the impact of a missense variant located within a membrane. On a dataset of 2,078 pathogenic and 1,060 benign variants, spanning 711 proteins from 706 structures, Missense3D-TM achieved an accuracy of 66%, Mathews correlation coefficient of 0.37, sensitivity of 58% and specificity of 81%. Missense3D-TM performed similarly to mCSM-membrane: accuracy 66% vs 61% (p = 0.02) on an unbalanced test set and 70% vs 67% (p = 0.20) on a balanced test set. The Missense3D-TM website provides an analysis of the structural effects of the variant along with its predicted position within the membrane. The web server is available at http://missense3d.bc.ic.ac.uk/.2024-01-01T00:00:00Z2024 Jan2026-06-02T07:22:44.203Z2025-07-05T03:04:13.424ZS-EPMC76175223818230110.1016/j.jmb.2023.168374