HLA-DRB3

Summary

HLA-DRB3 (major histocompatibility complex, class II, DR beta 3, HGNC:4951) is a protein-coding gene on chromosome 6p21.3 alternate reference locus, encoding HLA class II histocompatibility antigen, DR beta 3 chain (P79483). A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule.

HLA-DRB3 belongs to the HLA class II beta chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DRA) and a beta (DRB) chain, both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells. The beta chain is approximately 26-28 kDa and its gene contains 6 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and exon 5 encodes the cytoplasmic tail. Within the DR molecule the beta chain contains all the polymorphisms specifying the peptide binding specificities. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. There are multiple pseudogenes of this gene.

Source: NCBI Gene 3125 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Druggable target: yes
• MANE Select transcript: NM_022555

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4951
Approved symbol	HLA-DRB3
Name	major histocompatibility complex, class II, DR beta 3
Location	6p21.3 alternate reference locus
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000196101
OMIM	612735
Entrez	3125

Gene structure

Transcript identifiers

Ensembl transcripts: 0

RefSeq mRNA: 1 — MANE Select: NM_022555 NM_022555

Canonical transcript exons

ENST00000307137 — 0 exons

Expression profiles

Bgee: expression breadth broad, 19 present calls, max score 97.53.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2769 / max 38.8763, expressed in 120 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72976	0.2769	120

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lung	UBERON:0002048	97.53	gold quality
material anatomical entity	UBERON:0000465	91.00	gold quality
anatomical system	UBERON:0000467	90.59	gold quality
optic choroid	UBERON:0001776	83.99	gold quality
spleen	UBERON:0002106	81.10	gold quality
nasopharynx	UBERON:0001728	77.25	gold quality
stomach	UBERON:0000945	74.98	gold quality
mammary gland	UBERON:0001911	73.79	gold quality
pancreas	UBERON:0001264	73.53	gold quality
islet of Langerhans	UBERON:0000006	72.15	gold quality
thymus	UBERON:0002370	68.17	gold quality
eye	UBERON:0000970	62.68	gold quality
hypothalamus	UBERON:0001898	58.13	gold quality
brain	UBERON:0000955	55.98	gold quality
uterus	UBERON:0000995	55.84	gold quality
artery	UBERON:0001637	55.75	silver quality
aorta	UBERON:0000947	54.97	silver quality
heart	UBERON:0000948	54.14	silver quality
adult mammalian kidney	UBERON:0000082	52.53	silver quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	1545.17
E-CURD-46	yes	590.63
E-GEOD-89232	yes	326.30
E-MTAB-7316	yes	13.97
E-MTAB-6678	yes	9.05
E-MTAB-7606	no	771.58

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CIITA, RFX5, RFXANK, RFXAP

Literature-anchored findings (GeneRIF, showing 40)

• analysis of coding sequences and haplotypic associations of HLA-B and HLA-DRB1 and association to HLA-DRB3 and HLA-DRB4 loci (PMID:15896200)
• HLA-DR3 is associated with anti-cyclic citrullinated peptide antibody-negative arthritis and not with anti-CCP-positive arthritis (PMID:16200610)
• HLA-DR3 alleles are associated with anti-CCP- disease and with lower levels of anti-CCP antibodies (PMID:16320316)
• The HLA-DR locus seems to be associated with the genetic susceptibility to develop SNP in Mexicans. (PMID:16815190)
• very pronounced distribution bias (P<10(-5)) of the two major DR3 conserved extended haplotypes, with DR3-B18 predominating in type 1 diabetes and DR3-B8 in celiac disease (PMID:16929349)
• German patients were distinct from Italian and North American patients with respect to DQ2 and from the North American patients with respect to B8-DR3-DQ2 HLA in autoimmune hepatitis (AIH) type 1. (PMID:17006990)
• HLA-DR and INS VNTR alleles mark both type 1 diabetes disease susceptibility and separate Caucasian parental subpopulations (PMID:17052889)
• DRB3*0101 and DRB1*0301 belong to an ancestral haplotype and are associated with many autoimmune diseases linked to antigen presentation. (PMID:17583734)
• DR3 is strongly associated with ulcerative colitis protection in a Spanish population. (PMID:17714554)
• The researchers found an association between HLA-DR3 and the presence of anti-Ro/La antibodies in patients with SLE. (PMID:17910142)
• No particular HLA-DR and DQ alleles, as well as tumor necrosis factor alpha and CTLA-4 genotypes, were associated with CAID. (PMID:18223493)
• HLA-DR3 allele may influence susceptibility to the sporadic inclusion body myositis. (PMID:18258695)
• Risk of type I diabetes in individuals with extended DR3 haplotype 8.1 is genotype-dependent, possibly associated with DPB1 and HLA class I loci. (PMID:18486765)
• T-cell responses associated with neonatal alloimmune thrombocytopenia: isolation of HPA-1a-specific, HLA-DRB3*0101-restricted CD4+ T cells (PMID:19136661)
• This study showed that significant expression of HLA-DRB3 genotypes in patients with human high-grade gliomas in Sicily. (PMID:19487887)
• interactions between Tg and discrete HLA-DR pocket signatures contribute to the initiation of autoimmune thyroid disease (PMID:19776016)
• results suggest that DRB3 plays a significant role in antigen presentation with different epitopic preferences to DRB1. (PMID:19830726)
• CatG cleaves human leukocyte antigen (HLA)-DR in vitro. Cleavage occurred on the loop between fx1 and fx2 of the membrane-proximal beta2 domain. In vivo, however, the CatG cleavage site is sterically inaccessible or masked by associated molecules. (PMID:20331476)
• IA2 positivity was associated with HLA-DR4/X and HLA-DR3/4 positivity, and hypothyroidism was linked to HLA-DR4/4. (PMID:20371654)
• Patients with Wolfram syndrome have a different profile of the HLA antigens with the presence of DR2, DQw1 and DRB3/4 allele and are negative for diabetes-related autoantibodies (PMID:21447263)
• All patients with sporadic inclusion body myositis carried the HLA-DRB1*0301 allele, or its equivalent HLA-DR3 serological specificity (PMID:21507567)
• TNF associations with type 1 diabetes are caused by their linkage disequilibrium with specific HLA-DR3-DQ2 haplotypes in the Indian population. (PMID:22366579)
• In addition to confirming one of the top findings in the meta-analysis, TRIM26, RNF5 and HLA-DRB3 have been identified as potential candidate genes for schizophrenia. (PMID:22433715)
• There are no significant differences in the HLA-DRB3/B4/B5 homozygosity and heterozygosity rates between Korean males and females in both newborns and adults. (PMID:22531795)
• Heterozygosity of HLA-DRB3*01:01 and HLA-DRB4*01:01 as a potential predictor of fetal neonatal alloimmune thrombocytopenia. (PMID:22671039)
• There was a strong sporadic inclusion body myositis association with the carriage of the DRB3*01:01 allele which was accounted for by its linkage disequilibrium with DRB1*03:01. (PMID:23010279)
• Three sets of HLA-DR3-positive haplotypes are designed that provide maximum risk of type 1 diabetes development in Indians and suggest a common Caucasian ancestor from which multiple haplotypes evolve independently. (PMID:23387390)
• HLA-DRB3*02:02 on the DRB1*03:01 haplotype can contribute to type 1 diabetes risk. (PMID:23462545)
• Prospective evaluation of matching for HLA-DRB3/4/5, -DQ, and -DP loci is warranted to reduce posttransplant risks in donor-recipient pairs matched for 7/8 HEL. (PMID:23596045)
• The unusual DRB1*08:01 haplotype carrying DRB3*02:02 has been confirmed in a Dutch family. (PMID:23742216)
• Haplotyping was done on 91 Southern Europe celiac patients. HLA-DR3-DQ2 without HLA-DR7-DQ2 was present in 62.6%, HLA-DR7-DQ2 without HLA-DR3-DQ2 was present in 16.5% and HLA-DR4-DQ8 without HLA-DQ2 was present in 3.3%. (PMID:24628273)
• Children with the HLA haplotype DR3-DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. (PMID:24988556)
• this mouse model unravels a critical role for HLA-DR3 in generating an autoimmune response to SmD and lupus nephritis in the NZM2328 background. (PMID:26475924)
• HLA-DRB3 affects type 1 diabetes risk and islet autoantibodies. (PMID:26740600)
• The first time that the haplotypes A33-DR3 and A33-DR9 were found with an enhanced predisposition to type 1 diabetes in Han Chinese. (PMID:27181214)
• In contrast to HLA-DRB4*01:01P, the inheritance of HLA-DRB3*01:01 is strongly associated with the propensity for mounting a humoral immune response against fetal HPA-1a antigen. (PMID:28019029)
• our findings provide clear evidence that the HLA-DRB1*15:01 and HLA-DRB3*02:02 alleles independently and strongly associate with phospholipase A2 receptor related idiopathic membranous nephropathy in the Chinese population (PMID:28028136)
• Characterization of the novel HLA-DRB3*02:02:25 allele by sequencing-based typing. (PMID:32462780)
• Characterization of the novel HLA-DRB3*03:49 allele by sequencing-based typing. (PMID:33565267)
• Full genomic sequence of the HLA-DRB3*02:32 allele by Single Molecule Real-time Sequencing Technology. (PMID:36286990)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

HLA class II histocompatibility antigen, DR beta 3 chain — P79483 (reviewed: P79483)

Alternative names: MHC class II antigen DRB3

All UniProt accessions (1): P79483

UniProt curated annotations — full annotation on UniProt →

Function. A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the alpha chain HLA-DRA, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DRB3-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. ALLELE DRB301:01: Exclusively presents several immunogenic epitopes derived from C.tetani neurotoxin tetX, playing a significant role in immune recognition and long-term protection. Presents viral epitopes derived from HHV-6B U11, TRX2/U56 and U85 antigens to polyfunctional CD4-positive T cells with cytotoxic activity implicated in control of HHV-6B infection. ALLELE DRB302:02 Exclusively presents several immunogenic epitopes derived from C.tetani neurotoxin tetX, playing a significant role in immune recognition and long-term protection. Upon EBV infection, presents to CD4-positive T cells latent antigen EBNA2 (PRSPTVFYNIPPMPLPPSQL) and lytic antigen BZLF1 (LTAYHVSTAPTGSWF) peptides, driving oligoclonal expansion and selection of virus-specific memory T cell subsets with cytotoxic potential to directly eliminate virus-infected B cells. Presents viral epitopes derived from HHV-6B U11, gB/U39 and gH/U48 antigens to polyfunctional CD4-positive T cells with cytotoxic activity implicated in control of HHV-6B infection. Plays a minor role in CD4-positive T cell immune response against Dengue virus by presenting conserved peptides from capsid and non-structural NS3 proteins. Displays peptides derived from IAV matrix protein M, implying a role in protection against IAV infection. In the context of tumor immunesurveillance, may present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies. Presents to Vbeta2-positive T-helper 1 cells specifically an immunodominant peptide derived from tumor antigen CTAG1A/NY-ESO-1(PGVLLKEFTVSGNILTIRLTAADHR) and confers protective memory response. In metastatic epithelial tumors, presents to intratumoral CD4-positive T cells a TP53 neoantigen (HYNYMCNSSCMGSMNRRPILTIITL) carrying G245S hotspot driver mutation and may mediate tumor regression. ALLELE DRB3*03:01: Presents a series of conserved peptides derived from the M.tuberculosis PPE family of proteins, in particular PPE29 and PPE33, known to be highly immunogenic. Presents immunogenic epitopes derived from C.tetani neurotoxin tetX, playing a role in immune recognition and long-term protection. Displays immunodominant viral peptides from HCV non-structural protein NS2, as part of a broad range T-helper response to resolve infection.

Subunit / interactions. Heterotrimer that consists of an alpha chain HLA-DRA, a beta chain HLA-DRB1 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 with TCR (via CDR3). Interacts (via beta-2 domain) with CD4 coreceptor (via Ig-like V-type domain); this interaction is of exceptionally low affinity yet necessary for optimal recognition of antigenic peptides.

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

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

Post-translational modifications. Ubiquitinated by MARCHF1 and MARCHF8 at Lys-254 leading to sorting into the endosome system and down-regulation of MHC class II.

Domain organisation. The beta-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 alpha-1 domain of HLA-DRA. Forms hydrogen bonds with the peptide main chain via conserved amino acid in most HLA-DRB molecules. The polymorphic residues accomodate the side chains of the peptide conferring peptide specificity to distinct HLA-DRB3 alleles. The peptide-bound beta-1 domain forms hydrogen bonds with CDR2 and CDR3 alpha-domains of TCR. The beta-2 Ig-like domain mediates the interaction with CD4 coreceptor.

Polymorphism. Highly polymorphic. Polymorphic residues encode for the beta-1 domain of the peptide-binding cleft, where they contribute to variations in peptide binding and TCR recognition among different alleles. The sequence shown is that of DRB301:01. The sequences of common representative alleles of serologically distinct allele groups as defined in the catalog of common and well-documented HLA alleles, are described as variants of DRB301:01. The most frequent alleles in human population are DRB301:01 (DR52a), DRB302:02 (DR52b) and DRB303:01 (DR52c). Allele DRB301:01 belongs to an ancestral haplotype and is associated with autoimmune diseases that are linked to antigen presentation. It is found in more than 95% of the homozygous HPA-1B mothers that produce anti-HPA-1A antibodies, leading to neonatal alloimmune thrombocytopenia (NAIT). In the context of hematological malignancy and T cell transplantation, alleles DRB301:01 and DRB302:02 present minor histocompatibility antigens derived respectively from host PTK2B and MR1 proteins, contributing to T cell-mediated graft-versus-leukemia effect and complete remission. Allele DRB3*03:01 plays an important role in the outcome of HLA-identical sex-mismatched organ transplantation. Presents to T-helper cells a minor histocompatibility antigen encoded by the Y chromosome RPS4Y1 (VIKVNDTVQI), leading to the maturation of dendritic cells and expansion of antigen-specific cytotoxic T cells, ultimately triggering transplant rejection.

Similarity. Belongs to the MHC class II family.

RefSeq proteins (1): NP_072049* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000353	MHC_II_b_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: PF00969, PF07654

UniProt features (80 total): sequence variant 42, strand 13, site 5, helix 5, turn 4, disulfide bond 2, topological domain 2, region of interest 2, signal peptide 1, chain 1, glycosylation site 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3C5J	X-RAY DIFFRACTION	1.8
2Q6W	X-RAY DIFFRACTION	2.25
4H1L	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P79483-F1	89.24	0.73

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 (5): 100 (self-peptide antigen); 110 (self-peptide antigen); 111 (self-peptide antigen); 40 (self-peptide antigen); 90 (self-peptide antigen)

Disulfide bonds (2): 44–108, 146–202

Glycosylation sites (1): 48

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: 173 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, MODULE_97, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOCC_VACUOLAR_MEMBRANE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, BIOCARTA_TCRA_PATHWAY, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, MODULE_182, GAURNIER_PSMD4_TARGETS, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_ANTIGEN, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY

GO Biological Process (14): adaptive immune response (GO:0002250), myeloid dendritic cell antigen processing and presentation (GO:0002469), peptide antigen assembly with MHC class II protein complex (GO:0002503), positive regulation of T cell mediated immune response to tumor cell (GO:0002842), signal transduction (GO:0007165), antigen processing and presentation of exogenous peptide antigen via MHC class II (GO:0019886), positive regulation of immune response (GO:0050778), T cell receptor signaling pathway (GO:0050852), positive regulation of T cell activation (GO:0050870), positive regulation of CD4-positive, alpha-beta T cell activation (GO:2000516), immune system process (GO:0002376), antigen processing and presentation of peptide or polysaccharide antigen via MHC class II (GO:0002504), immune response (GO:0006955), antigen processing and presentation (GO:0019882)

GO Molecular Function (4): MHC class II protein complex binding (GO:0023026), MHC class II receptor activity (GO:0032395), peptide antigen binding (GO:0042605), protein binding (GO:0005515)

GO Cellular Component (18): Golgi membrane (GO:0000139), lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), ER to Golgi transport vesicle membrane (GO:0012507), membrane (GO:0016020), transport vesicle membrane (GO:0030658), endocytic vesicle membrane (GO:0030666), clathrin-coated endocytic vesicle membrane (GO:0030669), late endosome membrane (GO:0031902), trans-Golgi network membrane (GO:0032588), MHC class II protein complex (GO:0042613), lumenal side of endoplasmic reticulum membrane (GO:0098553), autolysosome membrane (GO:0120281), lysosome (GO:0005764), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), 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
bounding membrane of organelle	3
immune response	2
antigen processing and presentation of peptide antigen via MHC class II	2
immune system process	2
cytoplasmic vesicle membrane	2
organelle membrane	2
endomembrane system	2
cytoplasm	2
dendritic cell antigen processing and presentation	1
MHC class II protein complex assembly	1
peptide antigen assembly with MHC protein complex	1
T cell mediated immune response to tumor cell	1
positive regulation of T cell mediated immunity	1
positive regulation of immune response to tumor cell	1
regulation of T cell mediated immune response to tumor cell	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
antigen processing and presentation of exogenous peptide antigen	1
positive regulation of immune system process	1
positive regulation of response to stimulus	1
regulation of immune response	1
antigen receptor-mediated signaling pathway	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
CD4-positive, alpha-beta T cell activation	1
positive regulation of alpha-beta T cell activation	1
regulation of CD4-positive, alpha-beta T cell activation	1
biological_process	1
antigen processing and presentation	1
response to stimulus	1
MHC protein complex binding	1
transmembrane signaling receptor activity	1
MHC class II protein binding	1
immune receptor activity	1
antigen binding	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

37 interactions, top by confidence:

A	B	Type	Score
CALR	HLA-DRB3	psi-mi:“MI:0915”(physical association)	0.560
HLA-DRB3	DLST	psi-mi:“MI:0915”(physical association)	0.560
	HLA-DRB3	psi-mi:“MI:0915”(physical association)	0.560
HLA-DRB3	NEK7	psi-mi:“MI:0915”(physical association)	0.560
CD74	HLA-DRA	psi-mi:“MI:0914”(association)	0.560
HLA-DRB3	HLA-DRB1	psi-mi:“MI:0914”(association)	0.530
HLA-DRB3	MAP3K13	psi-mi:“MI:0915”(physical association)	0.370
HLA-DRB3	CDCA8	psi-mi:“MI:0915”(physical association)	0.370
HLA-DRB3	ZDHHC17	psi-mi:“MI:0915”(physical association)	0.370
HLA-DRB3	C1QL1	psi-mi:“MI:0914”(association)	0.350
CLEC2D	ESYT2	psi-mi:“MI:0914”(association)	0.350
TMEM106A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-C	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-G	TMEM131L	psi-mi:“MI:0914”(association)	0.350
BTNL2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
KLRD1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-DQA1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HLA-DRB3	TMEM131L	psi-mi:“MI:0914”(association)	0.350
ASIC4	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SARAF	A2ML1	psi-mi:“MI:0914”(association)	0.350
CHST8	NDUFS8	psi-mi:“MI:0914”(association)	0.350

BioGRID (71): HLA-DRB1 (Affinity Capture-MS), SEPN1 (Affinity Capture-MS), SEMA4F (Affinity Capture-MS), HLA-DRB1 (Affinity Capture-MS), SEPN1 (Affinity Capture-MS), POMC (Co-crystal Structure), C1QL1 (Affinity Capture-MS), CNNM1 (Affinity Capture-MS), HLA-DRB1 (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), TMEM106B (Affinity Capture-MS), HLA-DRB3 (Affinity Capture-MS), HLA-DRB3 (Affinity Capture-MS), HLA-DRB3 (Affinity Capture-MS), HLA-DRB3 (Affinity Capture-MS)

ESM2 similar proteins: A0A140LHF2, D3YX43, O00241, O70394, P01854, P01855, P01871, P01874, P01875, P01876, P01877, P01878, P01879, P01880, P03988, P04221, P06336, P06337, P0C788, P0DOX2, P0DOX3, P0DOX4, P0DOX6, P0DUB3, P15464, P15983, P18211, P20756, P20758, P20768, P23084, P23085, P23086, P23087, P23088, P26952, P29826, P79483, Q15109, Q28173

Diamond homologs: O62848, P04440, P06126, P11609, P11610, P13762, P15812, P15813, P18470, P20756, P23042, P23043, P23068, P29016, P29017, P79483, P80943, Q07717, Q28565, Q29422, Q30154, Q4ACW4, Q5YB65, Q63493, Q8AYH8, Q9QZY5, Q9QZY6, Q9QZY7, Q9QZY8, Q9QZY9, Q9QZZ0, Q9QZZ1, Q9QZZ2, Q9XS72, A0M8Q6, B9A064, P01834, P01835, P01836, P01837

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
CIITA	“up-regulates quantity by expression”	HLA-DRB3	“transcriptional regulation”
MARCHF8	“down-regulates quantity by destabilization”	HLA-DRB3	polyubiquitination
MARCHF1	“down-regulates quantity by destabilization”	HLA-DRB3	polyubiquitination
“RFX complex”	“up-regulates quantity by expression”	HLA-DRB3	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 36 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	8	35.9×	4e-09
MHC class II antigen presentation	5	15.9×	2e-04
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	5	15.6×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
peptide antigen assembly with MHC class II protein complex	5	146.3×	2e-08
antigen processing and presentation of exogenous peptide antigen via MHC class II	6	90.6×	1e-08
positive regulation of T cell mediated cytotoxicity	5	70.9×	7e-07
positive regulation of immune response	5	66.9×	7e-07
positive regulation of T cell activation	5	61.6×	9e-07
adaptive immune response	7	16.4×	9e-06
immune response	8	10.5×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

0 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	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000878606 (6:32522494 C>T), RS1001168152 (6:32523792 G>A), RS1001724928 (6:32517653 G>A,T), RS1003190068 (6:32529767 A>T), RS1003428619 (6:32529680 T>C), RS1004098245 (6:32527596 G>T), RS1004741283 (6:32519899 G>A), RS1005414021 (6:32517899 A>T), RS1008014728 (6:32528230 C>A,G,T), RS1008140870 (6:32521400 A>G), RS1014017637 (6:32527573 A>G), RS1014877946 (6:32526023 T>C), RS1016852371 (6:32527598 C>T), RS1019319406 (6:32529075 C>A), RS1019960642 (6:32530930 A>G)

Disease associations

OMIM: gene MIM:612735 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005005_41	Plantar warts	2.000000e-30

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008406	susceptibility to plantar warts measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3460 (SINGLE PROTEIN), CHEMBL3988561 (PROTEIN FAMILY)

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
HLA-DRB3*01:01	Toxicity	3	heparin	Heparin-induced thrombocytopenia
HLA-DRB3*02:02	Toxicity	3	clozapine	Schizophrenia

ChEMBL bioactivities

19 potent at pChembl≥5 of 22 total, top 19 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.51	IC50	31	nM	CHEMBL57315
7.30	IC50	50	nM	CHEMBL1790415
7.12	IC50	76	nM	CHEMBL2373036
7.00	IC50	100	nM	CHEMBL1790402
6.89	IC50	130	nM	CHEMBL2373033
6.79	IC50	162	nM	CHEMBL2373032
6.77	IC50	170	nM	CHEMBL2373029
6.75	IC50	178	nM	CHEMBL1793835
6.75	IC50	180	nM	CHEMBL291311
6.75	IC50	178	nM	CHEMBL2373031
6.53	IC50	293	nM	CHEMBL2373022
6.52	IC50	303	nM	CHEMBL1793835
6.37	IC50	424	nM	CHEMBL2373026
5.89	IC50	1300	nM	CHEMBL2373028
5.75	IC50	1800	nM	CHEMBL1790407
5.60	IC50	2500	nM	CHEMBL1790416
5.50	IC50	3150	nM	CHEMBL2373024
5.16	IC50	7000	nM	CHEMBL2373018
5.00	IC50	1e+04	nM	CHEMBL61199

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ceric oxide	decreases expression	1
iopromide	affects expression	1
cobalt oxide	decreases expression	1
STA 9090	increases expression	1
Allergens	affects cotreatment, increases expression	1
Vehicle Emissions	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Lovastatin	affects expression	1
Progesterone	affects cotreatment, decreases expression	1
Selenium	increases expression	1
Smoke	decreases expression	1
Vitamin E	increases expression	1
Antirheumatic Agents	decreases expression	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL660107	Binding	Ability to compete for binding to Class II MHC using ELISA assay.	Design of MHC class II (DR4) ligands using conformationally restricted imino acids at p3 and p5 — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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