SIGLEC16 encodes a sialic acid-binding immunoglobulin-like lectin that functions as an activating immune receptor, in contrast to its paired inhibitory counterpart SIGLEC11 1. The protein associates with the DAP12 adaptor protein and is expressed in macrophages and tissue macrophages, as well as human brain and cervical epithelium 12. SIGLEC16 recognizes sialylated glycans including polysialic acid and mediates proinflammatory signaling, promoting M1-like macrophage activation characterized by increased TNF and CD74 expression 3. The gene exists as both functional and nonfunctional alleles in human populations, with ~40-50% allele frequency for the wild-type form 13. Evolutionarily, SIGLEC16 and SIGLEC11 underwent complex gene conversions ~1-1.2 million years ago, likely contributing to hominin brain evolution 4. Clinically, patients with glioblastoma carrying functional SIGLEC16 alleles with polySia-positive tumors show improved overall survival due to enhanced antitumor immune activation 3. Additionally, functional SIGLEC16 variants correlate with protection against Neisseria gonorrhoeae infection, suggesting pathogen-driven selection 2. SIGLEC16 may serve as a diagnostic marker in inflammatory conditions like Behçet's disease 5.