37: Prioritizing missense variants with chemoproteomic-detected amino acids

Palafox MF et al., The American Journal of Human Genetics - This episode explores a multi-omic study showing that mass spectrometry–based chemoproteomic detection of cysteine, lysine, and tyrosine (CpDAAs) highlights protein sites and regions enriched for pathogenic missense variants and variant uncertainty. Key terms: chemoproteomics, missense_variants, CpDAA, fumarate_hydratase, variant_interpretation. Study Highlights:The authors assembled curated chemoproteomic datasets profiling cysteine, lysine, and tyrosine reactivity across the human proteome and mapped CpDAAs to monogenic-disease genes, ClinVar variants, and protein structures. CpD proteins are enriched for OMIM disease genes, missense constraint, and protein-protein interactions, and CpDAAs are significantly closer to pathogenic missense variants in both 1D sequence windows and 3D structure. Lysine- and tyrosine-detected residues show the strongest enrichment for proximal pathogenic variants, while cysteine environments harbor many VUSs and pathogenic alleles. A case study of fumarate hydratase (FH) demonstrates that CpDAA-proximal variants cluster in 3D and that mutations at detected cysteines alter FH oligomerization. Conclusion:Integrating chemoproteomic amino-acid reactivity with genetic and structural data can help prioritize likely functional and druggable missense variants, complementing existing variant-effect predictors. Music:Enjoy the music based on this article at the end of the episode. Article title:Prioritizing disease-associated missense variants with chemoproteomic-detected amino acids First author:Palafox MF Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2025.04.017 Reference:Palafox MF, Boatner L, Wilde BR, Christofk H, Backus KM, Arboleda VA. Prioritizing disease-associated missense variants with chemoproteomic-detected amino acids. The American Journal of Human Genetics. 2025;112:1–15. doi:10.1016/j.ajhg.2025.04.017 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/chemoproteomics-missense-variants-cpdaas QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-06. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the scientific content presented in the transcript: CpDAA concept, 1D and 3D proximity analyses, FH case study with tetramerization, implications for variant interpretation and covalent drug targeting, and acknowledged limitations.- transcript topics: Introduction to CpDAA concept and chemoproteomics; CpDAA mapping to disease-relevant genes (OMIM, ClinVar, FDA targets); 1D proximity analysis (6-amino-acid windows around CpDAAs); 3D proximity analysis (8-Å radius around CpDAAs in protein structures); Fumarate hydratase (FH) case study and Cys333/Cys434 CpDAA neighborhood; VUS, CADD scoring, and enrichment patterns by amino-acid type QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 5- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- CpDAAs defined as reactive cysteine...