ArticleBiophysical journal2023
Interpreting the molecular mechanisms of disease variants in human transmembrane proteins.
Article in Biophysical journal, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 31 citations in OpenAlex.
- Deep phenotyping of EHMT1 ankyrin repeat domain missense variants in Kleefstra syndrome by multi-tiered structural genomics analyses at atomic resolution.Human molecular genetics · 2026Article
- Bridging local-global transmembrane protein contexts with contrastive pretraining for alignment-free pathogenicity prediction.Briefings in bioinformatics · 2026Article
- Allostery is a widespread cause of loss-of-function variant pathogenicity.Nature communications · 2026Article
- MAVISp: A modular structure-based framework for protein variant effects.Protein science : a publication of the Protein Society · 2026Article
- Unlocking Protein Evolution Insights: Efficient and Interpretable Mutational Effect Predictions with GEMME.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Energetic and structural control of polyspecificity in a multidrug transporter.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Generalizable and scalable protein stability prediction with rewired protein generative models.Nature communications · 2025Article
- A small molecule stabilizer rescues the surface expression of nearly all missense variants in a GPCR.Nature structural & molecular biology · 2025Article
- Classification models distinguish functional and trafficking effects of KCNQ1 variants to enhance variant interpretation.bioRxiv : the preprint server for biology · 2025Article
- Prediction of pathogenic mutations in human transmembrane proteins and their associated diseases via utilizing pre-trained Bio-LLMs.Communications biology · 2025Article
- Expert-guided protein language models enable accurate and blazingly fast fitness prediction.Bioinformatics (Oxford, England) · 2024Article
- Illuminating the function of the orphan transporter, SLC22A10, in humans and other primates.Nature communications · 2024Article
- Article
- Alignment-based Protein Mutational Landscape Prediction: Doing More with Less.Genome biology and evolution · 2023Article
- Genome mining yields putative disease-associated ROMK variants with distinct defects.PLoS genetics · 2023Article
- Illuminating the Function of the Orphan Transporter, SLC22A10 in Humans and Other Primates.Research square · 2023Article
- Incorporating physics to overcome data scarcity in predictive modeling of protein function: A case study of BK channels.PLoS computational biology · 2023Article
- Illuminating the Function of the Orphan Transporter, SLC22A10 in Humans and Other Primates.bioRxiv : the preprint server for biology · 2023Article
- Incorporating physics to overcome data scarcity in predictive modeling of protein function: a case study of BK channels.bioRxiv : the preprint server for biology · 2023Article
- Membranes in focus.Biophysical journal · 2023Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Next-generation sequencing of human genomes reveals millions of missense variants, some of which may lead to loss of protein function and ultimately disease. Here, we investigate missense variants in membrane proteins-key drivers in cell signaling and recognition. We find enrichment of pathogenic variants in the transmembrane region across 19,000 functionally classified variants in human membrane proteins. To accurately predict variant consequences, one fundamentally needs to understand the underlying molecular processes. A key mechanism underlying pathogenicity in missense variants of soluble proteins has been shown to be loss of stability. Membrane proteins, however, are widely understudied. Here, we interpret variant effects on a larger scale by performing structure-based estimations of changes in thermodynamic stability using a membrane-specific energy function and analyses of sequence conservation during evolution of 15 transmembrane proteins. We find evidence for loss of stability being the cause of pathogenicity in more than half of the pathogenic variants, indicating that this is a driving factor also in membrane-protein-associated diseases. Our findings show how computational tools aid in gaining mechanistic insights into variant consequences for membrane proteins. To enable broader analyses of disease-related and population variants, we include variant mappings for the entire human proteome.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.