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To identify homologous gene clusters, computational tools that account for multi-gene architectures are needed to group gene clusters into Gene Cluster Families (GCFs). However, existing GCF delineation methods do not scale well to large datasets and are often limited to certain subclasses of gene clusters. Here, we present IGUA (Iterative Gene clUster Analysis; https:\/\/github.com\/zellerlab\/IGUA), a scalable, flexible GCF delineation method for genomic segments with multi-gene architectures. On a biosynthetic gene cluster (BGC) clustering task, IGUA is 29\u00d7 and 10\u00d7 faster than the state-of-the-art (BiG-SCAPE v2 and BiG-SLiCE v2, respectively; 28 CPUs), without sacrificing accuracy. To highlight its scalability, we use IGUA to cluster &amp;gt;2.8 million BGCs from \u22481 million prokaryotic genomes in &amp;lt;18 h (n = 2 829 071 BGCs to 56 960 GCFs). To showcase its utility beyond BGC clustering, we use IGUA to cluster five additional prokaryotic gene cluster types (secretion systems, prophages, genomic islands, phage-plasmids, and carbohydrate active enzyme [CAZyme] gene clusters). Overall, IGUA represents a versatile GCF delineation tool with unmatched computational efficiency and flexibility, enabling (meta)genomic mining applications at unprecedented scales.<\/jats:p>","DOI":"10.1093\/nar\/gkag975","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:42:17Z","timestamp":1790682137000},"source":"Crossref","is-referenced-by-count":0,"title":["Fast, flexible gene cluster family delineation with IGUA"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3947-4444","authenticated-orcid":false,"given":"Martin","family":"Larralde","sequence":"first","affiliation":[{"name":"Molecular Systems Biology Unit, European Molecular Biology Laboratory (EMBL) , Heidelberg, Baden-W\u00fcrttemberg 69117 ,","place":["Germany"]},{"name":"Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center , Leiden, South Holland 2333ZA 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F\u00e9d\u00e9rale de Lausanne (EPFL) , Lausanne, Vaud 1015 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0771-8309","authenticated-orcid":false,"given":"Lucas","family":"Paoli","sequence":"additional","affiliation":[{"name":"Global Health Institute, School of Life Science, \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL) , Lausanne, Vaud 1015 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Zeller","sequence":"additional","affiliation":[{"name":"Molecular Systems Biology Unit, European Molecular Biology Laboratory (EMBL) , Heidelberg, Baden-W\u00fcrttemberg 69117 ,","place":["Germany"]},{"name":"Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center , Leiden, South Holland 2333ZA ,","place":["Netherlands"]},{"name":"Center for Microbiome Analyses and Therapeutics (CMAT), Leiden University Medical Center , Leiden, South Holland 2333ZA ,","place":["Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3677-0192","authenticated-orcid":false,"given":"Laura M","family":"Carroll","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Ume\u00e5 University , Ume\u00e5, V\u00e4sterbotten 90187 ,","place":["Sweden"]},{"name":"Science for Life Laboratory (SciLifeLab), Ume\u00e5 University , Ume\u00e5, V\u00e4sterbotten 90187 ,","place":["Sweden"]},{"name":"Laboratory for Molecular Infection Medicine Sweden (MIMS), Ume\u00e5 University , Ume\u00e5, V\u00e4sterbotten 90187 ,","place":["Sweden"]},{"name":"Ume\u00e5 Centre for Microbial Research (UCMR), Ume\u00e5 University , Ume\u00e5, V\u00e4sterbotten 90187 ,","place":["Sweden"]},{"name":"Integrated Science Lab (IceLab), Ume\u00e5 University , Ume\u00e5, V\u00e4sterbotten 90187 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