B-P.43: Missense 3D portal, enabling investigation and interpretation of missense variants in their structural context
The expansion of the three-dimensional coverage of the human proteome and those of other organisms, achieved with AlphaFold, offers the unprecedented opportunity to assess the structural impact of millions of missense variants. The Missense3D Portal, freely available at https://missense3d.bc.ic.ac.uk/, is a suite of algorithms and databases that leverage the availability of experimental and modelled 3D structure, including protein complexes, to provide mechanistic explanations for the damaging effect of missense variants, such as disruption of chemical bonds and steric clashes.
Structural predictions for >9 million missense variants, produced by our core algorithm, Missense3D, are freely available through the Missense3d-αDB database and will soon be integrated into ProtVar at EBI. Furthermore, structural predictions for >4 million human variants, generated using experimental structures and 3D models produced with our Phyre2 homology modelling tool, are available from the Missense3D-DB database and integrated into DECIPHER at EBI.
Missense3D-PTM, published in JMB December 2025, is the latest addition to the Missense3D Portal. Developed as part of the UK Human Functional Genomics Initiative, it is a “one-stop-shop” for dynamically investigating missense variants in the context of post-translational modifications (PTMs). Its user-friendly web interface provides mapping of 11,490,257 naturally-occurring human missense variants and 334,255 PTM sites (spanning >50 PTM types, including phosphorylation, glycosylation, and sumoylation) along with their neighbouring residues in sequence and 3D structure space, using AlphaFold models for 20,431 proteins. Furthermore, precalculated distances in 3D space between any PTM and any residue, enable visualization and exploration of novel variants currently not included in the Missense3D-PTM database.
Co-authors: Ifigenia Tsitsa, Gordon Hanna, Anja Conev, Haotian Zhao, Grace Walker, Wendy Tran, Olivia Simmonds, Suhail Islam, Michael J E Sternberg, Alessia David
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