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A previously established loss-of-function mouse model of KS1 exhibits key phenotypic features, and therapeutic trials in this mouse model suggest postnatal malleability of neurological symptoms. However, 15-30% of individuals with KS1 carry missense variants. To investigate whether missense variants lead to similar phenotypic presentation in mice, we used CRISPR-Cas9 to introduce the KS1 patient variant R5179H, corresponding to R5230H in mice, into C57BL\/6NTac animals. Computational and in vitro testing suggested that the R5230H variant does not impair protein stability or enzyme function of KMT2D. Despite a distinct mechanistic basis, our new mouse model (Kmt2d+\/R5230H) recapitulated most phenotypes of our prior loss-of-function model, including growth deficiency, craniofacial anomalies and IgA deficiency, but not altered neurological function. Kmt2d+\/R5230H mice showed perinatal lethality and a high frequency of unilateral kidney agenesis, a novel phenotype in KS1 mouse models. Kmt2d+\/R5230H mice provide a unique opportunity to understand the impact of missense variants on KMT2D function and uncover developmental and perinatal abnormalities in KS1.<\/jats:p>","DOI":"10.1242\/dmm.052775","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:55:02Z","timestamp":1788944102000},"source":"Crossref","is-referenced-by-count":0,"title":["A patient-derived missense mouse model of Kabuki syndrome 1"],"prefix":"10.1242","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5844-5447","authenticated-orcid":false,"given":"Sara Tholl","family":"Halldorsdottir","sequence":"first","affiliation":[{"name":"The Louma G. 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