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All four proteins form CARD\u2010CC\/BCL10\/MALT1 (CBM) complexes leading to nuclear factor\u2010kappa\u2010B (NF\u2010\u03baB) activation after upstream phosphorylation by various protein kinase C (PKC) isoforms. CBM complex signaling is critical for innate and adaptive immunity, but aberrant activation can cause autoimmune or autoinflammatory diseases, or be oncogenic. CARD9 shows a superior auto\u2010inhibition compared with other CARD\u2010CC family proteins, with very low spontaneous activity when overexpressed in HEK293T cells. In contrast, the poor auto\u2010inhibition of other CARD\u2010CC family proteins, especially CARD10 (CARMA3) and CARD14 (CARMA2), is hampering characterization of upstream activators or activating mutations in overexpression studies. We grafted different domains from CARD10, 11, and 14 on CARD9 to generate chimeric CARD9 backbones for functional characterization of activating mutants using NF\u2010\u03baB reporter gene activation in HEK293T cells as readout. CARD11 (CARMA1) activity was not further reduced by grafting on CARD9 backbones. The chimeric CARD9 approach was subsequently validated by using several known disease\u2010associated mutations in CARD10 and CARD14, and additional screening allowed us to identify several previously unknown activating natural variants in human CARD9 and CARD10. Using Genebass as a resource of exome\u2010based disease association statistics, we found that activated alleles of\n                    <jats:italic>CARD9<\/jats:italic>\n                    correlate with irritable bowel syndrome (IBS), constipation, osteoarthritis, fibromyalgia, insomnia, anxiety, and depression, which can occur as comorbidities.\n                  <\/jats:p>","DOI":"10.1111\/febs.17035","type":"journal-article","created":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T02:05:37Z","timestamp":1702605937000},"page":"1220-1245","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Chimeric and mutant\n                    <scp>CARD9<\/scp>\n                    constructs enable analyses of conserved and diverged autoinhibition mechanisms in the\n                    <scp>CARD\u2010CC<\/scp>\n                    protein 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