HLA-DRA

Summary

HLA-DRA (major histocompatibility complex, class II, DR alpha, HGNC:4947) is a protein-coding gene on chromosome 6p21.32, encoding HLA class II histocompatibility antigen, DR alpha chain (P01903). An alpha chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In precision oncology, HLA-DRA EXPRESSION confers sensitivity to Nivolumab + Atezolizumab + Pembrolizumab in Skin Melanoma (CIViC Level B).

HLA-DRA is one of the HLA class II alpha chain paralogues. This class II molecule is a heterodimer consisting of an alpha and a beta chain, both anchored in the membrane. This molecule is expressed on the surface of various antigen presenting cells such as B lymphocytes, dendritic cells, and monocytes/macrophages, and plays a central role in the immune system and response by presenting peptides derived from extracellular proteins, in particular, pathogen-derived peptides to T cells. The alpha chain is approximately 33-35 kDa and its gene contains 5 exons. Exon 1 encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, and exon 4 encodes the transmembrane domain and the cytoplasmic tail. DRA does not have polymorphisms in the peptide binding part and acts as the sole alpha chain for DRB1, DRB3, DRB4 and DRB5.

Source: NCBI Gene 3122 — RefSeq curated summary.

At a glance

• GWAS associations: 137
• Clinical variants (ClinVar): 9 total
• Phenotypes (HPO): 7
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_019111

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4947
Approved symbol	HLA-DRA
Name	major histocompatibility complex, class II, DR alpha
Location	6p21.32
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000204287
Ensembl biotype	protein_coding
OMIM	142860
Entrez	3122

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000374982, ENST00000395388, ENST00000870694, ENST00000870695, ENST00000870696, ENST00000870697, ENST00000917299

RefSeq mRNA: 1 — MANE Select: NM_019111 NM_019111

CCDS: CCDS4750

Canonical transcript exons

ENST00000383127 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 99.89.

FANTOM5 (CAGE): breadth broad, TPM avg 480.6760 / max 24211.2147, expressed in 801 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67137	477.4673	798
67140	1.0784	268
67138	0.6013	207
67146	0.5489	182
67139	0.5332	192
67141	0.4469	180

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.89	gold quality
leukocyte	CL:0000738	99.88	gold quality
vermiform appendix	UBERON:0001154	99.88	gold quality
lymph node	UBERON:0000029	99.85	gold quality
granulocyte	CL:0000094	99.83	gold quality
gall bladder	UBERON:0002110	99.81	gold quality
duodenum	UBERON:0002114	99.73	gold quality
spleen	UBERON:0002106	99.72	gold quality
right lung	UBERON:0002167	99.70	gold quality
upper lobe of left lung	UBERON:0008952	99.70	gold quality
smooth muscle tissue	UBERON:0001135	99.62	gold quality
rectum	UBERON:0001052	99.58	gold quality
right coronary artery	UBERON:0001625	99.42	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.41	gold quality
small intestine Peyer’s patch	UBERON:0003454	99.37	gold quality
small intestine	UBERON:0002108	99.27	gold quality
adipose tissue	UBERON:0001013	99.22	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.22	gold quality
descending thoracic aorta	UBERON:0002345	99.18	gold quality
tibial nerve	UBERON:0001323	99.17	gold quality
thoracic mammary gland	UBERON:0005200	99.17	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.14	gold quality
blood	UBERON:0000178	99.11	gold quality
metanephros cortex	UBERON:0010533	99.06	gold quality
adult mammalian kidney	UBERON:0000082	98.99	gold quality
tonsil	UBERON:0002372	98.99	gold quality
fallopian tube	UBERON:0003889	98.99	gold quality
omental fat pad	UBERON:0010414	98.99	gold quality
colonic epithelium	UBERON:0000397	98.95	gold quality
bone marrow	UBERON:0002371	98.89	gold quality

Single-cell (SCXA)

Detected in 49 experiment(s), a significant marker in 45.

Experiment	Marker?	Max mean expression
E-CURD-126	yes	17617.81
E-GEOD-134144	yes	17055.25
E-HCAD-36	yes	14478.22
E-GEOD-84465	yes	11047.68
E-MTAB-6678	yes	7982.69
E-MTAB-8322	yes	7560.51
E-GEOD-89232	yes	7399.06
E-MTAB-6308	yes	7364.70
E-GEOD-130148	yes	6500.25
E-GEOD-124472	yes	6084.50
E-MTAB-10287	yes	5926.76
E-MTAB-8142	yes	5621.50
E-MTAB-8495	yes	5584.04
E-GEOD-76312	yes	5506.24
E-GEOD-130473	yes	5207.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CIITA, CREB1, EZH2, FOS, GLI2, HDAC1, HMGA1, HMGA2, ILF3, KMT2A, NFX1, POU2F1, POU2F2, RFX1, RFX5, RFXANK, RFXAP, YY1

miRNA regulators (miRDB)

38 targeting HLA-DRA, 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-6873-3P	100.00	71.42	2626
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-567	99.63	68.57	1219
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4728-3P	99.47	68.94	981
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-2054	99.20	68.89	1699
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-508-3P	98.66	69.62	887
HSA-MIR-5011-3P	98.63	64.81	638

Literature-anchored findings (GeneRIF, showing 40)

• P. gingivalis membrane vesicles apparently inhibited IFN-gamma-induced MHC class II (HLA-DRalpha) by disrupting the IFN-gamma signaling transduction pathway. (PMID:11854199)
• IFN-gamma-induced HLA-DRA expression was inhibited by nitric oxide (NO) and antioxidants such as superoxide dismutase, catalase, pyrrolidine dithiocarbamate, and N-acetylcysteine (PMID:12006557)
• The donor TNFRSF6 polymorphism dierctly or indirectly influences acute kidney rejection episodes. (PMID:14736971)
• different regions of the cytoplasmic tails are involved in the association and the recruitment of HLA-DR(A & B1) into different compartments. HLA-DP and -DR interact differently with the cytoskeleton. (PMID:14976194)
• Data show that Oct-1 occupies the endogenous HLA-DRA promoter when the HLA-DRA promoter is inactive in retinoblastoma protein-defective cells. (PMID:15105429)
• Overexpression of HLA-DRA is associated with ovarian and other cancers (PMID:15467430)
• Downregulation of HLA-DRA is associated with early intrahepatic recurrence of hepatocellular carcinoma (PMID:15688398)
• Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis. (PMID:17660530)
• frequency of HLA antigens was significantly increased suggesting that brain cavernoma susceptibility may be associated with HLA antigens (PMID:17662350)
• HLA-DR alpha 2 domain (sHLA-DRalpha2) induces negative signals by engaging TIRC7 on lymphocytes, inhibiting proliferation and inducing apoptosis in CD4+ and CD8+ T-cells via activation of the intrinsic pathway (PMID:18270567)
• DNMT1 and HLA-DRalpha are prognostic factors for hepatocelluar carcinoma. (PMID:18931722)
• although lysine 219 is absolutely required for modification of DRalpha, other features of the DRalpha tail act to limit the extent of ubiquitination. (PMID:19117940)
• T cell receptor view of HLA-DRA in pocket 9 shows that the arrangement of residues in this pocket promotes anchoring of either large aliphatic or aromatic amino acids at this position. (PMID:19648278)
• Findings show that Sug1 is crucial for regulating histone H3K4me3 and H3R17me2 at the cytokine inducible MHC-II and CIITA promoters. (PMID:19660582)
• Studies indicate that five SNPs showed genome-wide significant association with MS: HLA-DRA, IL7R, IL2RA, CD58 and CLEC16A. (PMID:19834503)
• Data show that pollen grains triggered the production of IL-8, TNF-alpha, IL-6 and strongly upregulated the membrane expression of CD80, CD86, CD83, HLA-DR and caused only a slight increase in the expression of CD40. (PMID:20118277)
• Continuous veno-venous hemofiltration is effective in removal of many plasma cytokines and in improvement of monocyte HLA-DR expression in septic patients. (PMID:20202859)
• predictive value of expression in diagnosis of acute promyelocytic leukemia (PMID:20232575)
• Upregulation of HLA-DRA is associated with acute pancreas allograft rejection. (PMID:20497195)
• The skeletal muscles of myasthenia gravis up regulation of MHC class @@. (PMID:20546939)
• HLA-DR4, PAD4 and STAT4 are overexpressed in rheumatoid arthritis and may be involved in the pathogenesis of RA. (PMID:20584675)
• HLA-DR(+) endothelial cells regulate the local inflammatory allogeneic response, promoting either an IL-6/STAT-3-dependent Th17 response or a contact-CD54-dependent regulatory response according to the cytokine environment. (PMID:21282653)
• This study indicated that the association between rs3129882 and parkinson disease remains unclear and requires further study. (PMID:21482477)
• The rs3129882 noncoding variant in intron 1 of HLA-DRA is associated with late-onset sporadic Parkinson disease in a Chinese Han population. (PMID:21791235)
• small interfering RNA-mediated knock-down of AIM2 resulted in reduced expression of HLA-DRA, HLA-DRB and CIITA in IFN-gamma-treated cells (PMID:21804607)
• Molecular Dynamics simulations of the MuBetaRho 83-99 (Phe91) and MuBetaRho 83-99 (Tyr91) peptide analogues in complex with HLA-DR2 (DRA, DRB1*1501) and T-cell receptors were performed. (PMID:21898163)
• SNP1 is a Parkinson’s disease-associated variant in HLA-DRA and is associated with HLA-DRA, DRB5 and DQA2 gene expression. (PMID:22096524)
• In this study observe no association between this single nucleotide polymorphism of HLA-DRA and Parkinson’s disease in a Taiwanese population. (PMID:22243834)
• genetic polymorphism is associated with the presence of nasal polyposis in asthmatic patients (PMID:22391069)
• Data indicate that 25 +/- 1.3% of CD74 and 17 +/- 0.3% of HLA-DR are colocalized. (PMID:22889831)
• 2 SNPs in the HLA-DRA gene were studied in Caucasian patients from 2 large studies of alcohol dependence. rs2239803 & rs4935356 were associated with AD in both cohorts. (PMID:22890421)
• The SNP rs3129882 in intron 1 of HLA-DRA has been shown to be most robustly associated with the Parkinson’s disease. (PMID:23083294)
• The HLA-DRA variation rs3129882 is not associated with Parkinson’s disease in Sweden.( (PMID:23579001)
• The expression of human leucocyte antigen (HLA)-DR in epithelial cells and cluster of differentiation (CD8)-positive lymphocytes as possible markers of chronic ocular graft versus host disease, was investigated. (PMID:23878500)
• The effects of rs11248051 and rs1564282 variants of GAK, and the rs3129882 variant of HLA-DRA, were investigated in Parkinson’s disease patients. (PMID:24039160)
• Data indicate five members of of DPbeta chains containing Lys-69 and GGPM 84-87, which assemble with DRalpha. (PMID:24214983)
• HLA-DOA, HLA-DRA, and HLA-DQA1 associated with spontaneous autoimmunity (PMID:24384427)
• suggest that binding of MAM to HLA-DR leads to a conformational change in MAM structure allowing its interaction with TLR2 and TLR4 and a better recognition by T cells. (PMID:24493819)
• Increased CD14+ monocytes with loss of HLA-DR expression were seen in patients with higher stage disease, more aggressive pathology, and in relapse or refractoriness to treatment. (PMID:24636145)
• This meta-analysis showed that the HLA-DRA rs3129882 A/G polymorphism was not a risk factor for Parkinson’s disease in Chinese. (PMID:24849299)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	H2-Ea	ENSMUSG00000036322
rattus_norvegicus	RT1-Da	ENSRNOG00000032844

Paralogs (13): B2M (ENSG00000166710), HLA-DQB1 (ENSG00000179344), HLA-DRB1 (ENSG00000196126), HLA-DQA1 (ENSG00000196735), HLA-DRB5 (ENSG00000198502), HLA-DOA (ENSG00000204252), HLA-DMA (ENSG00000204257), HLA-DPB1 (ENSG00000223865), HLA-DPA1 (ENSG00000231389), HLA-DQB2 (ENSG00000232629), HLA-DQA2 (ENSG00000237541), HLA-DOB (ENSG00000241106), HLA-DMB (ENSG00000242574)

Protein

Protein identifiers

HLA class II histocompatibility antigen, DR alpha chain — P01903 (reviewed: P01903)

Alternative names: MHC class II antigen DRA

All UniProt accessions (2): P01903, Q30118

UniProt curated annotations — full annotation on UniProt →

Function. An alpha chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the beta chain HLA-DRB, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DR-restricted CD4-positive T cells. This guides antigen-specific T-helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells. Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes. In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor-resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins. Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance. The selection of the immunodominant epitopes follows two processing modes: ‘bind first, cut/trim later’ for pathogen-derived antigenic peptides and ‘cut first, bind later’ for autoantigens/self-peptides. The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules.

Subunit / interactions. Heterotrimer that consists of an alpha chain HLA-DRA, a beta chain HLA-DRB and a peptide (peptide-MHCII). Newly synthesized alpha and beta chains forms a heterodimer (MHCII) that associates with the CD74/invariant chain (Ii) in the endoplasmic reticulum (ER). Ii is a trimer composed of three subunits and each subunit interacts with one MHCII dimer, blocking the peptide-binding cleft. As a result, MHCII molecules cannot bind peptides present in the ER. The complex of MHCII and CD74/Ii is transported in vesicles from ER to Golgi to lysosomes, where it encounters antigenic peptides generated via proteolysis of endocytosed antigens. MHCII dimers are dissociated from CD74/Ii by the combined action of proteolysis and HLA-DM. Lysosomal enzymes such as cathepsin, degrade CD74/Ii leaving a 24 amino acid remnant called class II-associated Ii or CLIP. Interacts (via the peptide binding cleft) with CLIP; this interaction inhibits antigen peptide binding before entry in the endosomal compartment. The displacement of CLIP and replacement by a high affinity peptide in lysosomes is performed by HLA-DM heterodimer. HLA-DM catalyzes CLIP dissociation from MHCII, stabilizes empty MHCII and mediates the selection of high affinity peptides. Interacts with HLA-DM heterodimer; this interaction is direct. Interacts (via alpha-1 domain) with TCR (via CDRs). Interacts (via alpha-2 domain) with CD4 (via Ig-like V-type domain); this interaction increases the affinity of TCR for peptide-MHCII. (Microbial infection) Interacts with Epstein-Barr virus BZLF2/gp42. (Microbial infection) Interacts with Staphylococcus aureus enterotoxin A/entA, enterotoxin B/entB, enterotoxin C1/entC1, enterotoxin D/entD, and enterotoxin H/entH.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane. Early endosome membrane. Late endosome membrane. Lysosome membrane. Autolysosome membrane.

Tissue specificity. Expressed in professional APCs: macrophages, dendritic cells and B cells (at protein level). Expressed in thymic epithelial cells (at protein level).

Post-translational modifications. Ubiquitinated by MARCHF1 or MARCHF8 at Lys-244 leading to down-regulation of MHCII. When associated with ubiquitination of the beta chain at ‘Lys-254’, the down-regulation of MHCII may be highly effective.

Domain organisation. The alpha-1 domain is a structural part of the peptide-binding cleft. It contains one alpha helix and 4 beta sheets, respectively forming part of the wall and the floor of the peptide-binding cleft. The other 4 beta sheets of the floor and the second alpha helix wall is formed by the beta-1 domain of HLA-DRB. Forms hydrogen bonds with the peptide main chain via conserved amino acids. The peptide-bound alpha-1 domain forms hydrogen bonds with CDR2 and CDR3 alpha-domain of TCR. The alpha-2 Ig-like domain mediates the interaction with CD4 coreceptor.

Induction. Up-regulated in dendritic cells upon maturation.

Polymorphism. The following alleles of DRA are known: DRA01:01 and DRA01:02. The sequence shown is that of DRA*01:02.

Similarity. Belongs to the MHC class II family.

RefSeq proteins (1): NP_061984* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001003	MHC_II_a_N	Domain
IPR003006	Ig/MHC_CS	Conserved_site
IPR003597	Ig_C1-set	Domain
IPR007110	Ig-like_dom	Domain
IPR011162	MHC_I/II-like_Ag-recog	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014745	MHC_II_a/b_N	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050160	MHC/Immunoglobulin	Family

Pfam: PF00993, PF07654

UniProt features (71 total): mutagenesis site 15, strand 15, sequence conflict 12, site 9, turn 3, region of interest 3, glycosylation site 2, topological domain 2, sequence variant 2, helix 2, signal peptide 1, chain 1, disulfide bond 1, cross-link 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

140 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5NI9	X-RAY DIFFRACTION	1.33
4X5W	X-RAY DIFFRACTION	1.34
5NIG	X-RAY DIFFRACTION	1.35
8CMC	X-RAY DIFFRACTION	1.42
8PJF	X-RAY DIFFRACTION	1.48
6QZC	X-RAY DIFFRACTION	1.64
8CMG	X-RAY DIFFRACTION	1.64
8CMH	X-RAY DIFFRACTION	1.64
4MD5	X-RAY DIFFRACTION	1.65
4MDJ	X-RAY DIFFRACTION	1.7
8PJE	X-RAY DIFFRACTION	1.7
7YX9	X-RAY DIFFRACTION	1.76
3C5J	X-RAY DIFFRACTION	1.8
8PJG	X-RAY DIFFRACTION	1.83
8CMB	X-RAY DIFFRACTION	1.84
1FV1	X-RAY DIFFRACTION	1.9
6ATF	X-RAY DIFFRACTION	1.9
6R0E	X-RAY DIFFRACTION	1.91
1KLU	X-RAY DIFFRACTION	1.93
3PDO	X-RAY DIFFRACTION	1.95
4MD4	X-RAY DIFFRACTION	1.95
6HBY	X-RAY DIFFRACTION	1.95
6ATI	X-RAY DIFFRACTION	1.98
5JLZ	X-RAY DIFFRACTION	1.99
1D5M	X-RAY DIFFRACTION	2
1D5Z	X-RAY DIFFRACTION	2
2G9H	X-RAY DIFFRACTION	2
4MDI	X-RAY DIFFRACTION	2
6CPN	X-RAY DIFFRACTION	2
7NZE	X-RAY DIFFRACTION	2.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01903-F1	89.65	0.76

Antibody-complex structures (SAbDab): 3 — 8EUQ, 8VSJ, 9B7B

Functional residue map

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

Catalytic / active sites (9): 74 (self-peptide antigen); 76 (self- and pathogen-derived peptide antigen); 77 (self-peptide antigen); 78 (self- and pathogen-derived peptide antigen); 80 (pathogen-derived peptide antigen); 87 (self- and pathogen-derived peptide antigen); 94 (pathogen-derived peptide antigen); 101 (self- and pathogen-derived peptide antigen); 34 (self- and pathogen-derived peptide antigen)

Post-translational modifications (1): 244

Disulfide bonds (1): 132–188

Glycosylation sites (2): 103, 143

Mutagenesis-validated functional residues (15):

Position	Phenotype
65	impairs the interaction with hla-dm complex, clip dissociation and peptide exchange.
68	decreases the interaction with hla-dm complex and peptide exchange.
74	increases the interaction with hla-dm complex and peptide exchange.
76	impairs the interaction with hla-dm complex, clip dissociation and peptide exchange.
76	increases the interaction with hla-dm complex and peptide exchange.
78	decreases the interaction with hla-dm complex and peptide exchange.
79	increases the interaction with hla-dm complex and peptide exchange.
80	increases the interaction with hla-dm complex and peptide exchange. decreases the affinity of the interaction with tcr b
82	decreases the interaction with hla-dm complex and peptide exchange.
93	decreases the affinity of the interaction with tcr by more than five-fold.
115	decreases the interaction with cd4.
117	decreases the interaction with cd4.
121	decreases the interaction with hla-dm complex and peptide exchange.
125	impairs the interaction with hla-dm complex and peptide exchange.
244	almost no change in down-regulation of mhcii. no ubiquitination and complete loss of down-regulation of mhcii; when asso

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-202424	Downstream TCR signaling
R-HSA-202427	Phosphorylation of CD3 and TCR zeta chains
R-HSA-202430	Translocation of ZAP-70 to Immunological synapse
R-HSA-202433	Generation of second messenger molecules
R-HSA-2132295	MHC class II antigen presentation
R-HSA-389948	Co-inhibition by PD-1
R-HSA-877300	Interferon gamma signaling

MSigDB gene sets: 466 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, IIZUKA_LIVER_CANCER_EARLY_RECURRENCE, GOBP_COGNITION, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, MCLACHLAN_DENTAL_CARIES_UP, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOCC_VACUOLAR_MEMBRANE, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, BIOCARTA_TCRA_PATHWAY

GO Biological Process (17): positive regulation of T cell mediated cytotoxicity (GO:0001916), adaptive immune response (GO:0002250), myeloid dendritic cell antigen processing and presentation (GO:0002469), antigen processing and presentation of endogenous peptide antigen via MHC class II (GO:0002491), peptide antigen assembly with MHC class II protein complex (GO:0002503), antigen processing and presentation of peptide or polysaccharide antigen via MHC class II (GO:0002504), immune response (GO:0006955), antigen processing and presentation of exogenous peptide antigen via MHC class II (GO:0019886), positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation (GO:0032831), positive regulation of memory T cell differentiation (GO:0043382), regulation of T-helper cell differentiation (GO:0045622), positive regulation of immune response (GO:0050778), positive regulation of T cell activation (GO:0050870), cognition (GO:0050890), positive regulation of CD4-positive, alpha-beta T cell activation (GO:2000516), immune system process (GO:0002376), antigen processing and presentation (GO:0019882)

GO Molecular Function (6): MHC class II protein complex binding (GO:0023026), polysaccharide binding (GO:0030247), peptide antigen binding (GO:0042605), T cell receptor binding (GO:0042608), protein binding (GO:0005515), MHC class II receptor activity (GO:0032395)

GO Cellular Component (23): Golgi membrane (GO:0000139), immunological synapse (GO:0001772), lysosome (GO:0005764), lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), cell surface (GO:0009986), ER to Golgi transport vesicle membrane (GO:0012507), transport vesicle membrane (GO:0030658), endocytic vesicle membrane (GO:0030666), clathrin-coated endocytic vesicle membrane (GO:0030669), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), trans-Golgi network membrane (GO:0032588), MHC class II protein complex (GO:0042613), extracellular exosome (GO:0070062), lumenal side of endoplasmic reticulum membrane (GO:0098553), autolysosome membrane (GO:0120281), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), endosome membrane (GO:0010008), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
TCR signaling	4
Adaptive Immune System	1
Regulation of T cell activation by CD28 family	1
Interferon Signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
antigen processing and presentation of peptide antigen via MHC class II	3
bounding membrane of organelle	3
immune response	2
immune system process	2
regulation of immune response	2
cellular anatomical structure	2
cytoplasmic vesicle membrane	2
endosome membrane	2
organelle membrane	2
endomembrane system	2
positive regulation of leukocyte mediated cytotoxicity	1
T cell mediated cytotoxicity	1
regulation of T cell mediated cytotoxicity	1
positive regulation of T cell mediated immunity	1
dendritic cell antigen processing and presentation	1
antigen processing and presentation of endogenous peptide antigen	1
MHC class II protein complex assembly	1
peptide antigen assembly with MHC protein complex	1
antigen processing and presentation	1
response to stimulus	1
antigen processing and presentation of exogenous peptide antigen	1
CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1
regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1
positive regulation of CD4-positive, alpha-beta T cell differentiation	1
positive regulation of regulatory T cell differentiation	1
positive regulation of immune effector process	1
memory T cell differentiation	1
regulation of memory T cell differentiation	1
positive regulation of T cell differentiation	1
positive regulation of immune response	1
T-helper cell differentiation	1
regulation of CD4-positive, alpha-beta T cell differentiation	1
positive regulation of immune system process	1
positive regulation of response to stimulus	1
T cell activation	1
regulation of T cell activation	1
positive regulation of lymphocyte activation	1
positive regulation of leukocyte cell-cell adhesion	1
nervous system process	1
CD4-positive, alpha-beta T cell activation	1

Protein interactions and networks

STRING

2942 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HLA-DRA	HLA-DRB1	P01911	968
HLA-DRA	NFX1	Q12986	809
HLA-DRA	HLA-DRB5	Q30154	806
HLA-DRA	CIITA	P33076	750
HLA-DRA	BTNL2	Q9UIR0	749
HLA-DRA	RFX5	P48382	715
HLA-DRA	CD3D	P04234	712
HLA-DRA	CD4	P01730	708
HLA-DRA	LAG3	P18627	697
HLA-DRA	RFXANK	O14593	683
HLA-DRA	CD74	P04233	664
HLA-DRA	STAT1	P42224	657
HLA-DRA	RFX1	P22670	647
HLA-DRA	RFXAP	O00287	633
HLA-DRA	HLA-DQB2	P05538	617

IntAct

79 interactions, top by confidence:

A	B	Type	Score
HLA-DRA	HLA-DRB1	psi-mi:“MI:0914”(association)	0.880
HLA-DRA	HLA-DRB1	psi-mi:“MI:0407”(direct interaction)	0.880
HLA-DRB1	HLA-DRA	psi-mi:“MI:0407”(direct interaction)	0.880
ERLIN1	ERLIN2	psi-mi:“MI:0914”(association)	0.740
HLA-DMA	HLA-DRA	psi-mi:“MI:0914”(association)	0.620
HLA-DMA	HLA-DRB1	psi-mi:“MI:0915”(physical association)	0.590
CD74	HLA-DRA	psi-mi:“MI:0914”(association)	0.560
CD74	HLA-DRA	psi-mi:“MI:0915”(physical association)	0.560
SSBP2	CLEC18A	psi-mi:“MI:0914”(association)	0.530
HLA-DRA	ENTPD6	psi-mi:“MI:0914”(association)	0.530
HLA-DRB1	HLA-DRA	psi-mi:“MI:0915”(physical association)	0.520
HLA-DRA	TRAC	psi-mi:“MI:0915”(physical association)	0.400
HLA-DRB1		psi-mi:“MI:0915”(physical association)	0.400
PRUNE2	HLA-DRA	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (223): KIAA0922 (Affinity Capture-MS), ATP2B2 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), DCBLD2 (Affinity Capture-MS), NETO2 (Affinity Capture-MS), STIM1 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), PLXNA1 (Affinity Capture-MS), HLA-DRB1 (Affinity Capture-MS), HLA-DRB5 (Affinity Capture-MS), SCARB1 (Affinity Capture-MS), TMEM97 (Affinity Capture-MS), POMT2 (Affinity Capture-MS), SLC25A16 (Affinity Capture-MS), LNPEP (Affinity Capture-MS)

ESM2 similar proteins: A3KPA0, A5A6L6, A5D7C3, O60487, O70255, O88792, P01865, P01903, P01904, P01910, P04224, P04228, P14434, P14439, P14778, P15980, P22646, P23150, P53788, P57087, P59822, P97952, Q00954, Q02955, Q07699, Q17QN4, Q1WIM2, Q28740, Q2WGK2, Q30631, Q3TEW6, Q3V3F6, Q4PPC4, Q5EAB0, Q5R804, Q61730, Q62929, Q63621, Q66KX2, Q68FQ2

Diamond homologs: A0A0G2K7V7, C1ITJ8, O19477, O35799, P01885, P01888, P01889, P01893, P01894, P01895, P01896, P01897, P01898, P01899, P01900, P01901, P01902, P01903, P03991, P04223, P04228, P04439, P06140, P06339, P10321, P13747, P13748, P13749, P13750, P13751, P13752, P13753, P14426, P14427, P14428, P14429, P14430, P14431, P14432, P14435

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
CIITA	“up-regulates quantity by expression”	HLA-DRA	“transcriptional regulation”
“RFX complex”	“up-regulates quantity by expression”	HLA-DRA	“transcriptional regulation”
NFX1	“down-regulates quantity by repression”	HLA-DRA	“transcriptional regulation”
RFX5	“up-regulates quantity by expression”	HLA-DRA	“transcriptional regulation”
“EBV gH:gL:gp42”	“up-regulates activity”	HLA-DRA	binding
HLA-DRA	up-regulates	Membrane_fusion
MARCHF8	“down-regulates quantity by destabilization”	HLA-DRA	polyubiquitination
MARCHF1	“down-regulates quantity by destabilization”	HLA-DRA	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 58 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
Interferon gamma signaling	7	26.6×	5e-07
MHC class II antigen presentation	6	16.2×	7e-05

GO biological processes:

GO term	Partners	Fold	FDR
peptide antigen assembly with MHC class II protein complex	6	129.0×	7e-10
antigen processing and presentation of exogenous peptide antigen via MHC class II	7	77.7×	7e-10
positive regulation of immune response	6	59.0×	8e-08
positive regulation of T cell activation	6	54.3×	1e-07
adaptive immune response	6	10.3×	2e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

621 predictions. Top by Δscore:

Variant	Effect	Δscore
6:32442438:T:TA	acceptor_gain	1.0000
6:32442446:A:AG	acceptor_gain	1.0000
6:32442447:G:GG	acceptor_gain	1.0000
6:32442447:GA:G	acceptor_gain	1.0000
6:32442447:GAA:G	acceptor_gain	1.0000
6:32442737:TTTGA:T	donor_gain	1.0000
6:32442741:A:T	donor_gain	1.0000
6:32442744:G:GG	donor_gain	1.0000
6:32443182:CA:C	acceptor_loss	1.0000
6:32443183:A:AG	acceptor_gain	1.0000
6:32443184:G:C	acceptor_loss	1.0000
6:32443184:G:GA	acceptor_gain	1.0000
6:32443184:GT:G	acceptor_gain	1.0000
6:32443184:GTA:G	acceptor_gain	1.0000
6:32443184:GTAC:G	acceptor_gain	1.0000
6:32443184:GTACC:G	acceptor_gain	1.0000
6:32443352:G:T	donor_gain	1.0000
6:32443754:A:AG	acceptor_gain	1.0000
6:32443755:G:GG	acceptor_gain	1.0000
6:32443755:GA:G	acceptor_gain	1.0000
6:32442443:TTCAG:T	acceptor_loss	0.9900
6:32442444:TCA:T	acceptor_loss	0.9900
6:32442445:CA:C	acceptor_loss	0.9900
6:32442447:G:A	acceptor_loss	0.9900
6:32442447:GAAGA:G	acceptor_gain	0.9900
6:32442651:G:GT	donor_gain	0.9900
6:32442694:GTA:G	donor_loss	0.9900
6:32442695:T:C	donor_loss	0.9900
6:32442727:G:T	donor_gain	0.9900
6:32443172:ATGT:A	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000321440 (6:32439026 T>C), RS1001105789 (6:32442921 T>C), RS1001627549 (6:32443916 A>G), RS1002014506 (6:32444187 A>G), RS1004181694 (6:32441732 T>C), RS1005319141 (6:32442034 G>C), RS1006122813 (6:32443799 G>A), RS1006802388 (6:32441272 T>G), RS1007102725 (6:32439809 T>C,G), RS1008444944 (6:32439744 A>C,G), RS1008585710 (6:32445047 T>A), RS1008657858 (6:32445448 A>C), RS1008833273 (6:32441663 G>A), RS1009306964 (6:32441301 T>A,C), RS1010040788 (6:32439492 G>T)

Disease associations

OMIM: gene MIM:142860 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000989	Pruritus
HP:0001596	Alopecia
HP:0002209	Sparse scalp hair
HP:0002215	Sparse axillary hair
HP:0002225	Sparse pubic hair
HP:0007468	Perifollicular hyperkeratosis
HP:0100725	Lichenification

GWAS associations

137 associations (top):

Study	Trait	p-value
GCST000062_4	Multiple sclerosis	9.000000e-81
GCST000243_1	Ulcerative colitis	6.000000e-18
GCST000311_1	Ulcerative colitis	1.000000e-16
GCST000356_1	Anti-cyclic Citrullinated Peptide Antibody	5.000000e-07
GCST000623_4	Ulcerative colitis	4.000000e-15
GCST000662_5	Vitiligo	7.000000e-19
GCST000772_4	Parkinson’s disease	2.000000e-10
GCST000851_3	Hodgkin’s lymphoma	3.000000e-50
GCST000964_4	Ulcerative colitis	1.000000e-55
GCST001077_3	Cystic fibrosis severity	1.000000e-07
GCST001156_4	Systemic sclerosis	2.000000e-27
GCST001183_8	Asthma	5.000000e-13
GCST001387_2	Hodgkin’s lymphoma	4.000000e-31
GCST001494_1	Non-obstructive azoospermia	3.000000e-06
GCST001679_1	Complement C3 and C4 levels	4.000000e-72
GCST001701_2	Asthma	1.000000e-08
GCST001728_3	Ulcerative colitis	5.000000e-133
GCST001826_3	Lymphoma	2.000000e-10
GCST001876_6	Pubertal anthropometrics	9.000000e-07
GCST001891_3	Multiple sclerosis (OCB status)	6.000000e-15
GCST001892_4	Multiple sclerosis (OCB status)	1.000000e-16
GCST001942_21	Prostate cancer	5.000000e-09
GCST002094_1	Crohn’s disease	5.000000e-12
GCST002094_4	Crohn’s disease	3.000000e-12
GCST002217_4	Sjögren’s syndrome	9.000000e-37
GCST002297_1	Hepatitis B vaccine response	3.000000e-19
GCST002453_5	Ulcerative colitis	2.000000e-06
GCST002516_2	Frontotemporal dementia	6.000000e-09
GCST002518_1	Food antigen IgG levels	9.000000e-08
GCST002562_2	Vogt-Koyanagi-Harada syndrome	1.000000e-119

EFO canonical traits (27, from GWAS)

EFO ID	Trait name
EFO:0004984	complement C4 measurement
EFO:0001382	puberty
EFO:0005206	oligoclonal band measurement
EFO:0004645	response to vaccine
EFO:0005844	response to dietary antigen
EFO:0006319	HIV viral set point measurement
EFO:0007744	lung disease severity measurement
EFO:0007790	Epstein Barr virus nuclear antigen 1 IgG measurement
EFO:0004458	C-reactive protein measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007949	acute-on-chronic liver failure
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008002	physical activity measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0008380	perceived unattractiveness to mosquitos measurement
EFO:0004340	body mass index
EFO:0008405	susceptibility to hepatitis B infection measurement
EFO:0009589	worry measurement
EFO:0009268	family history of Alzheimer’s disease
EFO:0007789	BMI-adjusted waist circumference
EFO:0004531	urate measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004918	age at diagnosis
EFO:0008039	BMI-adjusted hip circumference
EFO:0004881	asparaginase hypersensitivity
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
HLA-DRA EXPRESSION	Nivolumab + Atezolizumab + Pembrolizumab	Skin Melanoma	Sensitivity/Response	CIViC B	EID985

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3135388	HLA-DRA		0.00	0
rs3129880	HLA-DRA		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases reaction, increases expression, decreases expression	3
Acetaminophen	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Dexamethasone	increases expression, affects cotreatment, decreases expression, decreases reaction	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	decreases expression	2
triphenyl phosphate	affects expression	1
pirinixic acid	decreases expression, increases activity, affects binding	1
trichostatin A	increases expression	1
sulforaphane	decreases expression	1
nickel chloride	increases expression, affects cotreatment	1
iopromide	affects expression	1
chrysin	decreases expression	1
tamibarotene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
incobotulinumtoxinA	increases expression	1
Bortezomib	decreases expression	1
Dimethyl Fumarate	decreases reaction, increases expression	1
Rosiglitazone	decreases expression	1
Temozolomide	decreases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	decreases expression	1
Arsenic	decreases expression	1
Asbestos	increases expression	1

Cellosaurus cell lines

9 cell lines: 4 spontaneously immortalized cell line, 3 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_9W22	BLS-1.DR4	Transformed cell line	Male
CVCL_9W23	BLS-1.DR5	Transformed cell line	Male
CVCL_B8HG	Abcam HCT 116 HLA-DRA KO	Cancer cell line	Male
CVCL_B8WU	Abcam MCF-7 HLA-DRA KO	Cancer cell line	Female
CVCL_B9JR	Abcam A-549 HLA-DRA KO	Cancer cell line	Male
CVCL_V069	DAP.3-DR1	Spontaneously immortalized cell line	Male
CVCL_V070	DAP.3-DR4	Spontaneously immortalized cell line	Male
CVCL_V119	LDR2a	Spontaneously immortalized cell line	Male
CVCL_V120	LDR2b	Spontaneously immortalized cell line	Male

Clinical trials (associated diseases)

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