The human AGER (RAGE) gene lies within the major histocompatibility complex class III region on chromosome 6, which contains genes involved in immune responses, such as TNFalpha, lymphotoxin, complement components and homeobox gene HOX12. It comprises 11 exons and 10 introns, and a 5 flanking region that regulates its transcription. The resulting transcribed mRNA of ~1.4 kb with a short 3UTR is alternatively spliced, and nearly twenty isoforms have been identified in different tissues such as lung, liver, kidney, smooth muscle, endothelial cells and brain. The different RAGE gene splice variants have been named RAGE, RAGE_v1 to RAGE_v19 according to the Human Gene Nomenclature Committee. RAGE is composed of a number of distinct protein domains; an extracellular region (aa 1-342) composed of a signal peptide (aa 1-22), followed by three immunoglobulin-like domains, a V-type domain, (aa 23-116) and two C type domains (C1: aa 124-221 and C2: 227-317), a single transmembrane domain (aa 343-363), and a short cytoplasmic domain (aa 364-404) necessary for signaling. The prevalent isoforms of RAGE are full length RAGE, RAGE_v1 or endogenous secretory (es RAGE) which lacks the cytosolic and transmembrane domains and therefore can be secreted into the extracellular space, and N-terminal truncated RAGE (RAGE_v2) which lacks N-terminal V domain and therefore cannot bind ligands. RAGE_v2 does not form mature protein. Through its ability to scavenge RAGE ligands, soluble RAGE isoforms (sRAGE) are believed to act a decoy receptor by regulating signaling mediated by activation of full length RAGE. Expression of isoforms is tissue specific, suggesting tight tissue-specific regulation of expression. sRAGE can also be formed by ectodomain cleavage by ADAM10/MMP9.
A number of NF-kappaB sites have been identified in the RAGE 5 regulatory region. In addition, transcription is also controlled by other pro-inflammatory transcription factors such as SP-1 and AP-2.
At least 30 polymorphisms are known, most of which are single nucleotide polymorphisms (SNP). A Gly to Ser change at an N-glycosylation sequon at position 82, and two 5 flanking polymorphisms at position -374 and -429 lead to altered function and expression of RAGE.

RAGE is highly expressed during embryonic development, especially in the brain, but levels decrease in adult tissues. RAGE is found at low levels in neurons, endothelial cells, mononuclear phagocytes, smooth muscle cells, and constitutively expressed at high levels in the lung.

- Full length: membrane: single pass type I membrane protein.
- Isoforms: secreted.

Normal physiological functions of RAGE include embryonal neuronal growth, myogenesis, mobilization of dendritic cells, activation and differentiation of T cells, stem cell migration and osteoclast maturation. HMGB1 interaction of RAGE results in stimulation of myogenesis. RAGE mediates trophic and toxic effects of S100B on embryonal neurons, and promotes neurite outgrowth and neuronal regeneration promoted by HMGB1. RAGE also plays an important role in the regulation of osteoclast maturation and function, and bone remodeling.
Ligand interaction promotes activation of intracellular signaling pathways including the MAPK pathway, RAC-1 and CDC42, NADPH oxidase, PI3 kinase and JAK/STAT pathway, and activation of NF-kappaB. RAGE expression is induced in inflammatory settings, since its transcription is controlled by several transcription factors as mentioned above. Thus a positive feed-forward loop evolves in ligand rich inflammatory settings, perpetuating the pathology. sRAGE is believed to regulate signaling mediated by activation of full length RAGE. Binding of RAGE to HMGB1 induces RAGE shedding by ADAM10 metalloprotease, thus possibly representing another pathway for negatively regulating RAGE mediated cellular activation.