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/

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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, lysine, and tyrosine residues identified by chemoproteomics
- CpD proteins are enriched for OMIM monogenic-disease genes and FDA drug targets
- Pathogenic missense variants are proximal to CpDAAs in 1D space (near CpDAAs, e.g., within ~6 amino acids)
- Pathogenic missense variants are proximal to CpDAAs in 3D space (within ~8 Å)
- Lysine and tyrosine CpDAAs show stronger enrichment for proximal pathogenic variants than cysteine CpDAAs
- FH (fumarate hydratase) as a case study shows CpDAA environments near pathogenic/VUS variants and disruption of tetramerization

QC result: Pass.