{"doi":"10.1016/j.celrep.2024.114436","title":"Interface-guided phenotyping of coding variants in the transcription factor RUNX1","abstract":"Single-gene missense mutations remain challenging to interpret. Here, we deploy scalable functional screening by sequencing (SEUSS), a Perturb-seq method, to generate mutations at protein interfaces of RUNX1 and quantify their effect on activities of downstream cellular programs. We evaluate single-cell RNA profiles of 115 mutations in myelogenous leukemia cells and categorize them into three functionally distinct groups, wild-type (WT)-like, loss-of-function (LoF)-like, and hypomorphic, that we validate in orthogonal assays. LoF-like variants dominate the DNA-binding site and are recurrent in cancer; however, recurrence alone does not predict functional impact. Hypomorphic variants share characteristics with LoF-like but favor protein interactions, promoting gene expression indicative of nerve growth factor (NGF) response and cytokine recruitment of neutrophils. Accessible DNA near differentially expressed genes frequently contains RUNX1-binding motifs. Finally, we reclassify 16 variants of uncertain significance and train a classifier to predict 103 more. Our work demonstrates the potential of targeting protein interactions to better define the landscape of phenotypes reachable by missense mutations.","journal":"Cell Reports","year":2024,"id":465867,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9459,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":744623,"name":"Rebecca Panwala","orcid":"0000-0003-4749-9243","position":1,"is_corresponding":false},{"id":1190667,"name":"Jeanna Sheen","orcid":null,"position":2,"is_corresponding":false},{"id":646274,"name":"Kyle Ford","orcid":"0000-0002-9944-9216","position":3,"is_corresponding":false},{"id":675421,"name":"Nathan D. Jayne","orcid":"0000-0003-4868-7182","position":4,"is_corresponding":false},{"id":227597,"name":"Andrew Portell","orcid":"0000-0002-0757-909X","position":5,"is_corresponding":false},{"id":311115,"name":"Dong‐Er Zhang","orcid":"0000-0003-2541-6443","position":6,"is_corresponding":false},{"id":769383,"name":"Stephan Hütter","orcid":"0000-0003-2432-8898","position":7,"is_corresponding":false},{"id":323649,"name":"Torsten Haferlach","orcid":"0000-0003-0196-2837","position":8,"is_corresponding":false},{"id":1362,"name":"Trey Ideker","orcid":"0000-0002-1708-8454","position":9,"is_corresponding":false},{"id":62764,"name":"Prashant Mali","orcid":"0000-0002-3383-1287","position":10,"is_corresponding":false},{"id":2188,"name":"Hannah Carter","orcid":"0000-0002-1729-2463","position":11,"is_corresponding":false},{"id":404576,"name":"Kıvılcım Öztürk","orcid":"0000-0003-0159-8772","position":0,"is_corresponding":true}],"reference_count":151,"raw_metadata":null,"created_at":"2026-07-19T02:04:50.328230Z","pmid":"38968069","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}