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Here, we identify a somatic missense mutation, c.121G\u2009&gt;\u2009T (p.Gly41Cys) in <jats:italic>GJA4<\/jats:italic>, which encodes a transmembrane protein that is a component of gap junctions and hemichannels in the vascular system, in OCVM tissues from 25\/26 (96.2%) individuals with OCVM. GJA4 expression was detected in OCVM tissue including endothelial cells and the stroma, through immunohistochemistry. Within OCVM tissue, the mutation allele frequency was higher in endothelial cell-enriched fractions obtained using magnetic-activated cell sorting. Whole-cell voltage clamp analysis in <jats:italic>Xenopus<\/jats:italic> oocytes revealed that <jats:italic>GJA4<\/jats:italic> c.121G\u2009&gt;\u2009T (p.Gly41Cys) is a gain-of-function mutation that leads to the formation of a hyperactive hemichannel. Overexpression of the mutant protein in human umbilical vein endothelial cells led to a loss of cellular integrity, which was rescued by carbenoxolone, a non-specific gap junction\/hemichannel inhibitor. Our data suggest that <jats:italic>GJA4<\/jats:italic> c.121G\u2009&gt;\u2009T (p.Gly41Cys) is a potential driver gene mutation for OCVM. 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