HLA-G

Summary

HLA-G (major histocompatibility complex, class I, G, HGNC:4964) is a protein-coding gene on chromosome 6p22.1, encoding HLA class I histocompatibility antigen, alpha chain G (P17693). Non-classical major histocompatibility class Ib molecule involved in immune regulatory processes at the maternal-fetal interface.

HLA-G belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-G is expressed on fetal derived placental cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exon 6 encodes the cytoplasmic tail.

Source: NCBI Gene 3135 — RefSeq curated summary.

At a glance

• GWAS associations: 42
• Clinical variants (ClinVar): 15 total
• Phenotypes (HPO): 5
• MANE Select transcript: NM_001384290

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4964
Approved symbol	HLA-G
Name	major histocompatibility complex, class I, G
Location	6p22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000204632
Ensembl biotype	protein_coding
OMIM	142871
Entrez	3135

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000360323, ENST00000376815, ENST00000376818, ENST00000376828, ENST00000428701, ENST00000478355, ENST00000478519, ENST00000936944

RefSeq mRNA: 4 — MANE Select: NM_001384290 NM_001363567, NM_001384280, NM_001384290, NM_002127

CCDS: CCDS4668, CCDS87380

Canonical transcript exons

ENST00000360323 — 7 exons

Exon	Start	End
ENSE00001625800	29829418	29829693
ENSE00001653281	29829816	29829932
ENSE00001816786	29827825	29827917
ENSE00003487434	29830378	29830410
ENSE00003497682	29828543	29828818
ENSE00003518391	29828047	29828316
ENSE00003913282	29830768	29831021

Expression profiles

Bgee: expression breadth ubiquitous, 124 present calls, max score 95.38.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0589 / max 957.6143, expressed in 237 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66665	2.0589	237

Top tissues by expression

129 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	95.38	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.76	gold quality
pituitary gland	UBERON:0000007	81.58	gold quality
adenohypophysis	UBERON:0002196	81.11	gold quality
stromal cell of endometrium	CL:0002255	75.84	gold quality
duodenum	UBERON:0002114	75.05	gold quality
rectum	UBERON:0001052	73.57	gold quality
blood	UBERON:0000178	73.14	gold quality
upper lobe of left lung	UBERON:0008952	69.55	gold quality
right lung	UBERON:0002167	69.51	gold quality
granulocyte	CL:0000094	66.23	gold quality
lung	UBERON:0002048	64.86	gold quality
left testis	UBERON:0004533	63.99	gold quality
testis	UBERON:0000473	63.75	gold quality
spleen	UBERON:0002106	63.43	gold quality
right testis	UBERON:0004534	63.08	gold quality
bone marrow cell	CL:0002092	61.94	gold quality
vermiform appendix	UBERON:0001154	61.28	gold quality
mucosa of transverse colon	UBERON:0004991	58.07	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	58.03	gold quality
islet of Langerhans	UBERON:0000006	57.82	gold quality
small intestine	UBERON:0002108	57.27	gold quality
bone marrow	UBERON:0002371	56.59	gold quality
colonic epithelium	UBERON:0000397	56.55	silver quality
liver	UBERON:0002107	56.30	gold quality
small intestine Peyer’s patch	UBERON:0003454	56.21	gold quality
pancreas	UBERON:0001264	55.75	gold quality
tonsil	UBERON:0002372	55.72	gold quality
descending thoracic aorta	UBERON:0002345	55.65	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-24	yes	1258.35
E-MTAB-6678	yes	17.12
E-ANND-3	yes	9.31

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CIITA, GLI3, HIVEP2, HSF1, IRF1, MYC, MYCN, NFKB, NR4A3, PGR, RFX5, RREB1, SP1

miRNA regulators (miRDB)

54 targeting HLA-G, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• expression of HLA-G products in embryo cells is a mandatory, but not sufficient, prerequisite for the development of pregnancy. (PMID:11807769)
• Monocytes and T lymphocytes in HIV-1-positive patients express HLA-G molecule. (PMID:11834945)
• Soluble HLA class I molecules induce natural killer cell apoptosis through the engagement of CD8. HLA-A2, -Cw4, and -Bw46 alleles, or HLA-G1 leads to NK cell apoptosis. (PMID:11861287)
• Linkage disequilibrium and age estimates of a deletion polymorphism (1597DeltaC) in HLA-G suggest natural selection has acted on this allele (PMID:11975984)
• HLA-G exhibits low level of polymorphism in indigenous East Africans. (PMID:12039526)
• 1)MICA expressed in the M8 melanoma cell line triggered NK cell tumor lysis and 2) HLA-G1 coexpression mediated the inhibition of NK cytotoxicity by mitigating the MICA activating signal (PMID:12115588)
• HLA-G is co-expressed with CREB and CBP in extravillous cytotrophoblasts, revealing the in vivo relevance of this transactivation pathway (PMID:12183445)
• HLA-G inhibits the functions of murine dendritic cells via the PIR-B immune inhibitory receptor. (PMID:12207326)
• expression modulates cytokine production of monocyte generated dendritic cells (PMID:12232815)
• HLA-G class Ib genes reviewed; related locus discovered in Macaca mulatta and Papio anubis (PMID:12390864)
• HLA-G and maternal-fetal interface reviewed. Like the full-length HLA-G1, the HLA-G2, -G3, and -G4 truncated isoforms may be expressed at the cell surface and may modulate innate and acquired immune responses (PMID:12390865)
• HLA-G polymorphisms in couples with recurrent spontaneous abortions. (PMID:12392506)
• processing and transport to the cell surface [review] (PMID:12440768)
• HLA-G forms disulfide-linked dimers that are present on the cell surface. The disulfide linkage formed exclusively through Cys-42. (PMID:12454284)
• HLA-G might be activated by reversal of methylation-mediated repression during malignancy, inflammation, and allogenic reactions (PMID:12552087)
• HLA-G quality control depends on tapasin (PMID:12582157)
• NK cell receptor, KIR2DL4:HLA-G interaction is not essential for human reproduction. (PMID:12616484)
• Variation in the HLA-G promoter region influences miscarriage rates. (PMID:12721954)
• Soluble HLA-G1 may contribute to the control of implantation. Review. (PMID:12842408)
• inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G (PMID:12853576)
• Aberrant HLA-G expression is found at a relatively high frequency in renal cell carcinoma and might participate in evasion of these tumor cells from immunosurveillance. (PMID:12874014)
• HLA-G has developed a unique mechanism to enhance leukocyte Ig-like receptor-1 (LIR-1) binding and inhibitory function via expression of disulfide-linked oligomeric structures on the cell surface. (PMID:12874224)
• Whereas membrane HLA-G is found in extravillous trophoblasts, soluble HLA-G is observed in all placental trophoblasts, including villous cytotrophoblasts and syncitiotrophoblasts. (PMID:12874228)
• data demonstrate an indirect way of soluble HLA-G (HLA-G5) action on dendritic cells occurring via T lymphocytes (PMID:12878353)
• HLA-G expression is not a major immunological determinant of pregnancy maintenance among patients with idiopathic recurrent pregnancy loss (PMID:12900514)
• results suggest that the occurrence of pregnancy-associated diseases is strongly influenced by maternal sHLA-G plasma levels (PMID:12959223)
• HLA-G and IL-10 may play roles in the evasion of immunosurveillance in cutaneous lymphomas (PMID:14592815)
• functional homology to murine PED/Qa-2; localizes to lipid rafts (PMID:14602227)
• observed that HLA-G mRNAs having the 92-base deletion are more stable than the complete mRNA forms, suggesting this region may be involved in the mechanisms controlling post-transcriptional regulation of HLA-G molecule associated with allelic variants (PMID:14602228)
• demonstrated that complexes of HLA-G are present on the cell surface and further demonstrated that complexes of HLA-G might be present in a soluble form after interaction with ILT-2 (PMID:14602229)
• detection of high concentration of HLA-G in serum from liver-kidney transplant patients, but not in kidney transplant patients; the expression of HLA-G in graft biopsies is described (PMID:14602232)
• The detection of HLA-G protein in adult corneas leads to the conclusion that this protein may contribute to the maintenance of the privileged immune status of the cornea (PMID:14602233)
• reviewed present knowledge on the functional consequences of muscle-related HLA-G and concepts of its relevance under pathologic conditions (PMID:14602235)
• the presence of tolerogenic HLA-G molecules on melanoma-derived exosomes may provide a novel way for tumors to modulate host’s immune response (PMID:14602237)
• induction and expression in different skin cancer types - review (PMID:14602238)
• The frequency of the sHLA-G secretion associated to its inhibiting role on T cells and natural killer cells during tumoral lymphoid malignancies suggests a potential role of these molecules as escape mechanism from antitumoral response (PMID:14602240)
• The HLA-G molecule is not expressed in freshly isolated human leukemia cells. (PMID:14628085)
• Placental expression of two soluble HLA-G isoforms is demonstrated in placentas, with evidence that both soluble HLA-G isoforms decrease CD8 alpha expression in lymphocytes without stimulating cell death. (PMID:14634138)
• soluble HLA-G1 might play a role in the establishment of pregnancy by regulating cytokine release in concert with membrane-bound HLA-G1 (PMID:14638437)
• Upregulation of HLA-G expression correlates with malignant transformation in malignant melanocytic lesions, high inflammatory infiltration and HLA-A1 genotype (PMID:14639610)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-147g22.4	ENSDARG00000097275
danio_rerio	mhc1lia	ENSDARG00000097766
danio_rerio		ENSDARG00000115781

Paralogs (22): HFE (ENSG00000010704), FCGRT (ENSG00000104870), ULBP1 (ENSG00000111981), ULBP2 (ENSG00000131015), ULBP3 (ENSG00000131019), MR1 (ENSG00000153029), RAET1L (ENSG00000155918), CD1D (ENSG00000158473), CD1A (ENSG00000158477), CD1C (ENSG00000158481), CD1B (ENSG00000158485), CD1E (ENSG00000158488), AZGP1 (ENSG00000160862), RAET1E (ENSG00000164520), RAET1G (ENSG00000203722), MICB (ENSG00000204516), MICA (ENSG00000204520), HLA-C (ENSG00000204525), HLA-E (ENSG00000204592), HLA-F (ENSG00000204642), HLA-A (ENSG00000206503), HLA-B (ENSG00000234745)

Protein

Protein identifiers

HLA class I histocompatibility antigen, alpha chain G — P17693 (reviewed: P17693)

Alternative names: HLA G antigen, MHC class I antigen G

All UniProt accessions (5): P17693, Q29897, Q31611, Q5RJ85, Q6DU14

UniProt curated annotations — full annotation on UniProt →

Function. Non-classical major histocompatibility class Ib molecule involved in immune regulatory processes at the maternal-fetal interface. In complex with B2M/beta-2 microglobulin binds a limited repertoire of nonamer self-peptides derived from intracellular proteins including histones and ribosomal proteins. Peptide-bound HLA-G-B2M complex acts as a ligand for inhibitory/activating KIR2DL4, LILRB1 and LILRB2 receptors on uterine immune cells to promote fetal development while maintaining maternal-fetal tolerance. Upon interaction with KIR2DL4 and LILRB1 receptors on decidual NK cells, it triggers NK cell senescence-associated secretory phenotype as a molecular switch to promote vascular remodeling and fetal growth in early pregnancy. Through interaction with KIR2DL4 receptor on decidual macrophages induces pro-inflammatory cytokine production mainly associated with tissue remodeling. Through interaction with LILRB2 receptor triggers differentiation of type 1 regulatory T cells and myeloid-derived suppressor cells, both of which actively maintain maternal-fetal tolerance. May play a role in balancing tolerance and antiviral-immunity at maternal-fetal interface by keeping in check the effector functions of NK, CD8+ T cells and B cells. Reprograms B cells toward an immune suppressive phenotype via LILRB1. May induce immune activation/suppression via intercellular membrane transfer (trogocytosis), likely enabling interaction with KIR2DL4, which resides mostly in endosomes. Through interaction with the inhibitory receptor CD160 on endothelial cells may control angiogenesis in immune privileged sites. Likely does not bind B2M and presents peptides. Negatively regulates NK cell- and CD8+ T cell-mediated cytotoxicity. Likely does not bind B2M and presents peptides. Negatively regulates NK cell- and CD8+ T cell-mediated cytotoxicity. Likely does not bind B2M and presents peptides. Negatively regulates NK cell- and CD8+ T cell-mediated cytotoxicity. Non-classical major histocompatibility class Ib molecule involved in immune regulatory processes at the maternal-fetal interface. In complex with B2M/beta-2 microglobulin binds a limited repertoire of nonamer self-peptides derived from intracellular proteins including histones and ribosomal proteins. Peptide-bound HLA-G-B2M complex acts as a ligand for inhibitory/activating KIR2DL4, LILRB1 and LILRB2 receptors on uterine immune cells to promote fetal development while maintaining maternal-fetal tolerance. Upon interaction with KIR2DL4 and LILRB1 receptors on decidual NK cells, it triggers NK cell senescence-associated secretory phenotype as a molecular switch to promote vascular remodeling and fetal growth in early pregnancy. Through interaction with KIR2DL4 receptor on decidual macrophages induces pro-inflammatory cytokine production mainly associated with tissue remodeling. Through interaction with LILRB2 receptor triggers differentiation of type 1 regulatory T cells and myeloid-derived suppressor cells, both of which actively maintain maternal-fetal tolerance. Reprograms B cells toward an immune suppressive phenotype via LILRB1. Likely does not bind B2M and presents peptides. Likely does not bind B2M and presents peptides.

Subunit / interactions. Forms a heterotrimer with B2M and a self-peptide (peptide-bound HLA-G-B2M). HLA-G-B2M complex interacts with components of the antigen processing machinery TAPBP and TAP1-TAP2 complex; this interaction is required for loading of high affinity peptides and heterotrimer translocation to the cell surface. Interacts with CALCR; this interaction is required for appropriate folding. Interacts with COPB1; this interaction mediates the endoplasmic reticulum (ER) retrieval of HLA-G-B2M complexes that bind low affinity peptides. On the cell surface, peptide-bound HLA-G-B2M molecules (referred to as monomers) can form disulfide-linked homomultimers, homodimers and homotrimers. Interacts with KIR2DL4; this interaction is direct. Interacts with LILRB1 and LILRB2 receptors; this interaction is direct. Interacts with CD160; this interactions is direct. Interacts with CD8A homodimer; this interaction is direct and might down-regulate T cell receptor signaling. Isoform 2: Forms a non-disulfide-linked homodimer and interacts with LILRB2.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane. Early endosome membrane Secreted Cell membrane Cell membrane Cell membrane Secreted. Early endosome Secreted Secreted Cell projection. Filopodium membrane.

Tissue specificity. Expressed in adult eye. Expressed in immune cell subsets including monocytes, myeloid and plasmacytoid dendritic cells and regulatory T cells (Tr1)(at protein level). Secreted by follicular dendritic cell and follicular helper T cells. Detected in physiological fluids including amniotic fluid and serum. Expressed in placenta, amniotic membrane, skin, cord blood and peripheral blood mononuclear cells.

Post-translational modifications. N-glycosylated. Produced by proteolytic cleavage at the cell surface (shedding) by matrix metalloproteinase MMP2.

Domain organisation. The VL9 peptide/epitope (VMAPRTLFL) derived from the signal sequence is loaded onto HLA-E and enables HLA-E expression at the plasma membrane. Confers strong recognition by KLRD1-KLRC1 or KLRD1-KLRC2 receptors on NK cells.

Induction. Up-regulated by immunosuppressive cytokine IL10 on dendritic cells and CD4+ T cells. Up-regulated by progesterone in cytotrophoblasts.

Similarity. Belongs to the MHC class I family.

Isoforms (7)

UniProt ID	Names	Canonical?
P17693-1	1, HLA-G1	yes
P17693-2	2, HLA-G2
P17693-3	3, HLA-G3
P17693-4	4, HLA-G.3-5, HLA-G4
P17693-5	5, HLA-G1sol, HLA-G5
P17693-6	6, HLA-G2sol, HLA-G6
P17693-7	7, HLA-G7

RefSeq proteins (4): NP_001350496, NP_001371209, NP_001371219, NP_002118 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001039	MHC_I_a_a1/a2	Domain
IPR003006	Ig/MHC_CS	Conserved_site
IPR003597	Ig_C1-set	Domain
IPR007110	Ig-like_dom	Domain
IPR011161	MHC_I-like_Ag-recog	Domain
IPR011162	MHC_I/II-like_Ag-recog	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR037055	MHC_I-like_Ag-recog_sf	Homologous_superfamily
IPR050208	MHC_class-I_related	Family

Pfam: PF00129, PF07654

UniProt features (70 total): strand 20, binding site 10, splice variant 8, helix 8, region of interest 5, mutagenesis site 5, disulfide bond 4, chain 2, topological domain 2, signal peptide 1, short sequence motif 1, glycosylation site 1, transmembrane region 1, turn 1, domain 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
3KYO	X-RAY DIFFRACTION	1.7
1YDP	X-RAY DIFFRACTION	1.9
3KYN	X-RAY DIFFRACTION	2.4
2DYP	X-RAY DIFFRACTION	2.5
3BZE	X-RAY DIFFRACTION	2.5
6K60	X-RAY DIFFRACTION	3.15
2D31	X-RAY DIFFRACTION	3.2
6AEE	X-RAY DIFFRACTION	3.3
3CDG	X-RAY DIFFRACTION	3.4
3CII	X-RAY DIFFRACTION	4.41

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17693-F1	90.91	0.82

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (10): 31; 94; 101; 108; 167; 170; 179; 180; 183; 195

Disulfide bonds (4): 66, 125–188, 171, 227–283

Glycosylation sites (1): 110

Mutagenesis-validated functional residues (5):

Position	Phenotype
66	abolishes homodimerization and homotrimerization. decreases functional interaction with lilrb1. does not affect homodime
138	enables tapbp-independent transport to the cell surface.
138	decreases tapbp-dependent transport to the cell surface.
171	abolishes homodimerization. decreases functional interaction with lilrb1.
334–335	abolishes binding to copb1 and golgi-to-er retrograde transport.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1236974	ER-Phagosome pathway
R-HSA-1236977	Endosomal/Vacuolar pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-877300	Interferon gamma signaling
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-983170	Antigen Presentation: Folding, assembly and peptide loading of class I MHC

MSigDB gene sets: 436 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_DENDRITIC_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_TOLERANCE_INDUCTION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, REACTOME_ANTIGEN_PRESENTATION_FOLDING_ASSEMBLY_AND_PEPTIDE_LOADING_OF_CLASS_I_MHC, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOBP_REGULATION_OF_DENDRITIC_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION

GO Biological Process (27): negative regulation of T cell mediated cytotoxicity (GO:0001915), positive regulation of T cell mediated cytotoxicity (GO:0001916), peripheral B cell tolerance induction (GO:0002451), antigen processing and presentation of endogenous peptide antigen via MHC class Ib (GO:0002476), antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent (GO:0002486), positive regulation of tolerance induction (GO:0002645), positive regulation of T cell tolerance induction (GO:0002666), positive regulation of natural killer cell cytokine production (GO:0002729), immune response-inhibiting cell surface receptor signaling pathway (GO:0002767), immune response (GO:0006955), cellular defense response (GO:0006968), negative regulation of angiogenesis (GO:0016525), positive regulation of interleukin-12 production (GO:0032735), negative regulation of T cell proliferation (GO:0042130), protection from natural killer cell mediated cytotoxicity (GO:0042270), positive regulation of regulatory T cell differentiation (GO:0045591), negative regulation of natural killer cell mediated cytotoxicity (GO:0045953), negative regulation of immune response (GO:0050777), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), positive regulation of macrophage cytokine production (GO:0060907), protein homotrimerization (GO:0070207), negative regulation of G0 to G1 transition (GO:0070317), positive regulation of endothelial cell apoptotic process (GO:2000353), positive regulation of cellular senescence (GO:2000774), negative regulation of dendritic cell differentiation (GO:2001199), immune system process (GO:0002376), antigen processing and presentation of peptide antigen via MHC class I (GO:0002474)

GO Molecular Function (6): signaling receptor binding (GO:0005102), peptide antigen binding (GO:0042605), CD8 receptor binding (GO:0042610), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (19): Golgi membrane (GO:0000139), obsolete extracellular space (GO:0005615), early endosome (GO:0005769), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), ER to Golgi transport vesicle membrane (GO:0012507), membrane (GO:0016020), phagocytic vesicle membrane (GO:0030670), filopodium membrane (GO:0031527), early endosome membrane (GO:0031901), cis-Golgi network membrane (GO:0033106), MHC class I protein complex (GO:0042612), recycling endosome membrane (GO:0055038), lumenal side of endoplasmic reticulum membrane (GO:0098553), extracellular region (GO:0005576), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Antigen processing-Cross presentation	2
Interferon Signaling	2
Adaptive Immune System	1
SARS-CoV-2-host interactions	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
negative regulation of leukocyte mediated cytotoxicity	2
T cell mediated cytotoxicity	2
regulation of T cell mediated cytotoxicity	2
protein binding	2
bounding membrane of organelle	2
endosome membrane	2
endomembrane system	2
negative regulation of T cell mediated immunity	1
positive regulation of leukocyte mediated cytotoxicity	1
positive regulation of T cell mediated immunity	1
peripheral tolerance induction	1
B cell tolerance induction	1
B cell mediated immunity	1
antigen processing and presentation of peptide antigen via MHC class Ib	1
antigen processing and presentation of endogenous peptide antigen	1
antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway	1
tolerance induction	1
regulation of tolerance induction	1
positive regulation of immune system process	1
positive regulation of multicellular organismal process	1
T cell tolerance induction	1
positive regulation of tolerance induction	1
regulation of T cell tolerance induction	1
natural killer cell cytokine production	1
positive regulation of natural killer cell mediated immunity	1
positive regulation of cytokine production involved in immune response	1
regulation of natural killer cell cytokine production	1
immune response-inhibiting signal transduction	1
immune response-regulating cell surface receptor signaling pathway	1
immune system process	1
response to stimulus	1
defense response	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
positive regulation of cytokine production	1
interleukin-12 production	1
regulation of interleukin-12 production	1
T cell proliferation	1

Protein interactions and networks

STRING

1468 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HLA-G	LILRB1	Q8NHL6	997
HLA-G	KIR2DL4	P78400	996
HLA-G	LILRB2	Q8N423	996
HLA-G	KLRD1	Q13241	994
HLA-G	KLRC1	P26715	993
HLA-G	STAC	Q99469	992
HLA-G	CD160	O95971	985
HLA-G	CD8A	P01732	961
HLA-G	LILRB4	Q8NHJ6	859
HLA-G	HLA-E	P13747	781
HLA-G	KIR2DL3	P43628	768
HLA-G	IDO1	P14902	766
HLA-G	KLRC2	P26717	761
HLA-G	B2M	P01884	758
HLA-G	CD274	Q9NZQ7	737

IntAct

55 interactions, top by confidence:

A	B	Type	Score
HLA-G	LILRB2	psi-mi:“MI:0915”(physical association)	0.870
LILRB2	HLA-G	psi-mi:“MI:0915”(physical association)	0.870
LILRB2	HLA-G	psi-mi:“MI:0407”(direct interaction)	0.870
HLA-G	LILRB1	psi-mi:“MI:0915”(physical association)	0.830
HLA-G	LILRB1	psi-mi:“MI:0407”(direct interaction)	0.830
HLA-G	B2M	psi-mi:“MI:0915”(physical association)	0.780
HLA-G	HLA-G	psi-mi:“MI:0915”(physical association)	0.730
HLA-G	HLA-G	psi-mi:“MI:0407”(direct interaction)	0.730
B3GNT3	PGRMC1	psi-mi:“MI:0914”(association)	0.670
B2M	HLA-E	psi-mi:“MI:0915”(physical association)	0.590
B2M	TAPBP	psi-mi:“MI:0915”(physical association)	0.570
HLA-G	HLA-B	psi-mi:“MI:0914”(association)	0.530
PBXIP1	KCNN4	psi-mi:“MI:0914”(association)	0.530
SLC31A1	PRORP	psi-mi:“MI:0914”(association)	0.530
B2M	H2AX	psi-mi:“MI:0915”(physical association)	0.520
KLRD1	HLA-E	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (139): HLA-G (Affinity Capture-MS), HLA-C (Affinity Capture-MS), HLA-A (Affinity Capture-MS), HLA-F (Affinity Capture-MS), HLA-B (Affinity Capture-MS), HLA-E (Affinity Capture-MS), FAM213A (Affinity Capture-MS), HLA-G (Affinity Capture-MS), HLA-G (Affinity Capture-MS), HLA-G (Affinity Capture-Western), HLA-G (Reconstituted Complex), HLA-G (Reconstituted Complex), COPB1 (Affinity Capture-Western), HLA-G (Affinity Capture-MS), CD8A (Reconstituted Complex)

ESM2 similar proteins: O19477, O35799, P01899, P01901, P01902, P03991, P04223, P06339, P13599, P13747, P13752, P14426, P14427, P14429, P14430, P14432, P16212, P16391, P17693, P25311, P30383, P30385, P30386, P30387, P30516, P30517, P30686, P55899, P60018, P70387, Q29980, Q29983, Q2KN22, Q30201, Q3ZCH5, Q5RD09, Q61559, Q63678, Q64726, Q8HWB0

Diamond homologs: C1ITJ8, O19477, O35799, P01888, P01889, P01893, P01894, P01895, P01896, P01897, P01898, P01899, P01900, P01901, P01902, P03991, P04223, P04439, P06126, P06140, P06339, P10321, P13747, P13748, P13749, P13750, P13751, P13752, P13753, P13765, P14426, P14427, P14428, P14429, P14430, P14431, P14432, P15464, P15978, P15979

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
HLA-G	up-regulates	LILRB1	binding
CIITA	unknown	HLA-G	“transcriptional regulation”
MYC	“down-regulates quantity by repression”	HLA-G	“transcriptional regulation”
HLA-G	up-regulates	KLRC1	binding
HLA-G	up-regulates	KIR2DL4	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
DAP12 interactions	5	95.2×	4e-08
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	6	94.5×	2e-09
Interferon gamma signaling	7	35.1×	2e-08
ER-Phagosome pathway	6	31.1×	6e-07
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	8	27.9×	1e-08
SARS-CoV-2 activates/modulates innate and adaptive immune responses	5	17.8×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of T cell mediated cytotoxicity	5	91.2×	3e-07
adaptive immune response	8	24.1×	3e-07
immune response	6	10.1×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

15 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1440 predictions. Top by Δscore:

Variant	Effect	Δscore
6:29828796:G:GT	donor_gain	1.0000
6:29828796:G:T	donor_gain	1.0000
6:29829691:G:GT	donor_gain	1.0000
6:29829691:GGA:G	donor_gain	1.0000
6:29829692:GA:G	donor_gain	1.0000
6:29829692:GAG:G	donor_gain	1.0000
6:29829694:G:GG	donor_gain	1.0000
6:29829699:G:GT	donor_gain	1.0000
6:29829702:G:GT	donor_gain	1.0000
6:29830373:CACAG:C	acceptor_loss	1.0000
6:29830374:ACAG:A	acceptor_loss	1.0000
6:29830375:CAGA:C	acceptor_loss	1.0000
6:29830376:A:AG	acceptor_gain	1.0000
6:29830376:A:AT	acceptor_loss	1.0000
6:29830377:G:GG	acceptor_gain	1.0000
6:29830411:G:GG	donor_gain	1.0000
6:29827914:GCGG:G	donor_gain	0.9900
6:29828312:GGCCA:G	donor_gain	0.9900
6:29828313:GCCA:G	donor_gain	0.9900
6:29828313:GCCAG:G	donor_gain	0.9900
6:29828317:G:GG	donor_gain	0.9900
6:29828605:G:A	acceptor_gain	0.9900
6:29828709:GT:G	donor_gain	0.9900
6:29828740:A:T	donor_gain	0.9900
6:29828757:C:T	donor_gain	0.9900
6:29828781:A:G	donor_gain	0.9900
6:29828797:A:T	donor_gain	0.9900
6:29828800:G:GT	donor_gain	0.9900
6:29829414:TCA:T	acceptor_loss	0.9900
6:29829415:CA:C	acceptor_loss	0.9900

AlphaMissense

2190 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:29829492:T:C	F232L	0.986
6:29829494:C:A	F232L	0.986
6:29829494:C:G	F232L	0.986
6:29829591:T:C	F265L	0.971
6:29829593:C:A	F265L	0.971
6:29829593:C:G	F265L	0.971
6:29828151:T:C	F60L	0.967
6:29828153:C:A	F60L	0.967
6:29828153:C:G	F60L	0.967
6:29829519:T:A	W241R	0.953
6:29829519:T:C	W241R	0.953
6:29829521:G:C	W241C	0.948
6:29829521:G:T	W241C	0.948
6:29829477:T:A	C227S	0.936
6:29829478:G:C	C227S	0.936
6:29828109:T:C	F46L	0.928
6:29828111:C:A	F46L	0.928
6:29828111:C:G	F46L	0.928
6:29829645:T:A	C283S	0.927
6:29829646:G:C	C283S	0.927
6:29829493:T:C	F232S	0.925
6:29829477:T:C	C227R	0.923
6:29828668:T:A	W157R	0.920
6:29828668:T:C	W157R	0.920
6:29829602:G:C	W268C	0.919
6:29829602:G:T	W268C	0.919
6:29829645:T:C	C283R	0.918
6:29828142:T:C	F57L	0.906
6:29828144:C:A	F57L	0.906
6:29828144:C:G	F57L	0.906

dbSNP variants (sampled 300 via entrez): RS1000079385 (6:29825524 A>T), RS1000877756 (6:29831200 G>A), RS1001193818 (6:29824840 A>C), RS1001243158 (6:29825095 A>G), RS1001428984 (6:29830835 T>C), RS1004181336 (6:29829356 G>A,C,T), RS1004945092 (6:29825830 C>T), RS1005916313 (6:29830486 C>A,T), RS1006417225 (6:29824785 T>A), RS1007705583 (6:29830080 T>A), RS1010131947 (6:29824851 A>G), RS1010688900 (6:29828422 C>T), RS1011941129 (6:29827969 C>A,G,T), RS1014295200 (6:29826682 A>C), RS1014491362 (6:29826383 T>C)

Disease associations

OMIM: gene MIM:142871 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): post-COVID-19 disorder (MONDO:0100320)

Orphanet (0):

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001426	Non-Mendelian inheritance
HP:0002099	Asthma
HP:0032933	Airway hyperresponsiveness
HP:4000007	Bronchoconstriction

GWAS associations

42 associations (top):

Study	Trait	p-value
GCST001316_4	IgE levels	4.000000e-08
GCST001438_6	Crohn’s disease	2.000000e-10
GCST003991_18	Childhood ear infection	4.000000e-07
GCST004521_12	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_171	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_177	Autism spectrum disorder or schizophrenia	3.000000e-12
GCST004521_216	Autism spectrum disorder or schizophrenia	5.000000e-13
GCST004521_218	Autism spectrum disorder or schizophrenia	5.000000e-11
GCST004521_247	Autism spectrum disorder or schizophrenia	4.000000e-09
GCST004521_263	Autism spectrum disorder or schizophrenia	7.000000e-17
GCST004521_268	Autism spectrum disorder or schizophrenia	7.000000e-12
GCST004521_295	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_44	Autism spectrum disorder or schizophrenia	2.000000e-17
GCST004521_56	Autism spectrum disorder or schizophrenia	1.000000e-22
GCST004521_58	Autism spectrum disorder or schizophrenia	1.000000e-17
GCST004521_59	Autism spectrum disorder or schizophrenia	1.000000e-11
GCST004521_79	Autism spectrum disorder or schizophrenia	1.000000e-16
GCST004521_80	Autism spectrum disorder or schizophrenia	1.000000e-15
GCST004521_92	Autism spectrum disorder or schizophrenia	1.000000e-11
GCST004744_43	Lung adenocarcinoma	4.000000e-09
GCST005541_9	Sarcoidosis (Lofgren’s syndrome vs non-Lofgren’s syndrome)	7.000000e-16
GCST005990_55	Non-albumin protein levels	3.000000e-09
GCST006575_13	Takayasu arteritis	1.000000e-06
GCST007327_121	Smoking status (ever vs never smokers)	3.000000e-09
GCST007552_36	Colorectal cancer	7.000000e-09
GCST008575_3	IgM levels	1.000000e-21
GCST010241_58	Apolipoprotein A1 levels	1.000000e-14
GCST010242_341	HDL cholesterol levels	5.000000e-13
GCST010243_144	Apolipoprotein B levels	8.000000e-09
GCST010244_79	Triglyceride levels	2.000000e-09

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0007904	susceptibility to childhood ear infection measurement
EFO:0004318	smoking behavior
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004530	triglyceride measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

5 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1063320	Efficacy	3	HMG-CoA reductase inhibitors	Asthma
rs17179108	Efficacy	3	capecitabine;fluorouracil	Colorectal Neoplasms
rs371194629	Efficacy	3	capecitabine;fluorouracil	Colorectal Neoplasms
rs371194629	Efficacy	3	methotrexate	Rheumatoid arthritis
rs9380142	Efficacy	3	capecitabine;fluorouracil	Colorectal Neoplasms

PharmGKB variants

8 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1707	HLA-G		0.00	0
rs1710	HLA-G		0.00	0
rs1063320	HLA-G	3	1.25	1	HMG-CoA reductase inhibitors
rs1610696	HLA-G		0.00	0
rs9380142	HLA-G	3	3.25	1	capecitabine;fluorouracil
rs17179101	HLA-G		0.00	0
rs17179108	HLA-G	3	2.25	1	capecitabine;fluorouracil
rs371194629	HLA-G	3	2.75	2	capecitabine;fluorouracil;methotrexate

CTD chemical–gene interactions

60 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
bisphenol A	affects methylation, affects cotreatment, decreases methylation, decreases expression	3
Decitabine	affects expression, affects methylation, increases expression	3
Arsenic Trioxide	decreases expression	3
Progesterone	decreases reaction, increases expression	3
Tretinoin	increases expression	3
Fulvestrant	increases expression, affects cotreatment, decreases methylation, decreases reaction	2
Cisplatin	affects response to substance, affects cotreatment, increases expression	2
Estradiol	affects cotreatment, increases expression	2
Methotrexate	increases expression, affects response to substance, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	affects expression, affects cotreatment, increases expression	2
Mifepristone	increases expression, decreases reaction	2
bisphenol F	affects cotreatment, decreases methylation	1
sodium arsenate	increases abundance, increases expression	1
sulforaphane	decreases expression	1
cobaltous chloride	increases expression	1
2-ethylhexyldiphenylphosphate	decreases expression	1
glimepiride	affects expression	1
tamibarotene	increases expression	1
bifenthrin	decreases reaction, increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
NSC-87877	decreases reaction, increases activity, increases phosphorylation, decreases activity, decreases phosphorylation	1
dorsomorphin	affects cotreatment, increases expression	1
2,2,2,-trichloro-1-(3,4-dichlorophenyl)-ethylacetate	increases expression	1
3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol	decreases expression	1
Vorinostat	increases expression	1
Meropenem	affects expression	1
Angiotensin-Converting Enzyme Inhibitors	affects expression	1

Cellosaurus cell lines

15 cell lines: 11 cancer cell line, 2 spontaneously immortalized cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8HH	Abcam HCT 116 HLA-G KO	Cancer cell line	Male
CVCL_B9JS	Abcam A-549 HLA-G KO	Cancer cell line	Male
CVCL_D2FJ	Abcam MCF-7 HLA-G KO	Cancer cell line	Female
CVCL_E6QQ	Genomeditech CHO-K1 H_HLA-G+B2M	Spontaneously immortalized cell line	Female
CVCL_E6U3	Genomeditech HEK-293 H_HLA-G	Transformed cell line	Female
CVCL_E6W7	Genomeditech K-562 H_HLA-G+B2M	Cancer cell line	Female
CVCL_E6WK	Genomeditech MC-38 H_HLA-G+B2M	Cancer cell line	Female
CVCL_E6WQ	Genomeditech SK-OV-3 H_HLA-G	Cancer cell line	Female
CVCL_SR49	HAP1 HLA-G (-) 1	Cancer cell line	Male
CVCL_WK57	MAMIYA-HLAG	Cancer cell line

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.