<h4>Introduction</h4>Talaromyces marneffei can cause life-threatening disseminated infection, yet the immune alterations linking STAT1 gain-of-function (GOF) variants, including the previously reported L351F site, to talaromycosis remain incompletely defined.<h4>Methods</h4>We investigated STAT1-L351F in a four-member pedigree in which disease was restricted to the proband, combining human immunophenotyping, mechanistic assays, and an in vivo infection model. This evidence concerns the gene STAT1 and infection.