HLA-G Gene: Structure, Function, and Clinical Significance

HLA-G is a non-classical major histocompatibility complex (MHC) class I molecule encoded on chromosome 6p22.1. Unlike classical HLA class I genes, HLA-G exhibits limited polymorphism and is primarily expressed in immune-privileged tissues such as the placenta, thymus, and cornea. Its primary function is immunomodulation, including inhibition of natural killer (NK) cell and T-cell responses, induction of regulatory T cells, and promotion of maternal-fetal tolerance. Alternative splicing generates multiple isoforms (membrane-bound and soluble) that contribute to its diverse roles in pregnancy, transplantation, and cancer immune evasion.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (Reactome: R-HSA-198933)

• MHC class I antigen processing and presentation (Reactome: R-HSA-983170)

HLA-G is a 345-amino-acid glycoprotein (UniProt P17693) with three extracellular domains (α1, α2, α3), a transmembrane region, and a short cytoplasmic tail. It binds β2-microglobulin and presents peptides, but its primary function is immunomodulatory via interaction with inhibitory receptors (e.g., ILT2, ILT4, KIR2DL4) on NK cells, T cells, and antigen-presenting cells. Alternative splicing yields seven isoforms: four membrane-bound (HLA-G1 to -G4) and three soluble (HLA-G5 to -G7). Soluble HLA-G (sHLA-G) is detected in plasma and amniotic fluid. The protein is heavily glycosylated and forms disulfide-linked dimers that enhance receptor binding. Its expression is tightly regulated by epigenetic mechanisms and microRNAs.