HS3ST6 encodes heparan sulfate-glucosamine 3-sulfotransferase 6, a Golgi-localized sulfotransferase that catalyzes 3-O-sulfation of heparan sulfate using PAPS as the sulfate donor 1. This enzyme-mediated modification generates heparan sulfate capable of serving as a cellular receptor for Herpes Simplex Virus-1 entry 2. Unlike the related 3-OST-1, HS3ST6 does not generate anticoagulant heparan sulfate variants. HS3ST6 mutations cause hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH), a rare autosomal dominant disorder characterized by recurrent angioedema episodes 1. HS3ST6-associated HAE represents one of six genetic subtypes of HAE-nC1-INH, alongside mutations in F12, PLG, ANGPT1, KNG1, and MYOF 2. Clinical manifestations of HS3ST6-HAE include refractory angioedema with atypical, persistent lower extremity involvement extending beyond classical self-limiting presentations 3. Genetic screening for HS3ST6 mutations in patients with chr16 recurrent angioedema and normal C1-inhibitor enables identification of affected individuals and asymptomatic carriers at risk for life-threatening angioedema 4. Treatment with kallikrein inhibitors shows variable efficacy in HS3ST6 carriers, highlighting the need for individualized therapeutic approaches 3.