HLA-DQA1

Summary

HLA-DQA1 (major histocompatibility complex, class II, DQ alpha 1, HGNC:4942) is a protein-coding gene on chromosome 6p21.32, encoding HLA class II histocompatibility antigen, DQ alpha 1 chain (P01909). Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.

HLA-DQA1 belongs to the HLA class II alpha chain paralogues. The class II molecule is a heterodimer consisting of an alpha (DQA) and a beta chain (DQB), 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 (APC: B Lymphocytes, dendritic cells, macrophages). The alpha chain is approximately 33-35 kDa. It is encoded by 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. Within the DQ molecule both the alpha chain and the beta chain contain the polymorphisms specifying the peptide binding specificities, resulting in up to four different molecules. Typing for these polymorphisms is routinely done for bone marrow transplantation.

Source: NCBI Gene 3117 — RefSeq curated summary.

At a glance

• GWAS associations: 312
• Clinical variants (ClinVar): 45 total
• Phenotypes (HPO): 54
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_002122

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4942
Approved symbol	HLA-DQA1
Name	major histocompatibility complex, class II, DQ alpha 1
Location	6p21.32
Locus type	gene with protein product
Status	Approved
Aliases	CELIAC1
Ensembl gene	ENSG00000196735
Ensembl biotype	protein_coding
OMIM	146880
Entrez	3117

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000343139, ENST00000374949, ENST00000395363, ENST00000422863, ENST00000460633, ENST00000482745, ENST00000496318, ENST00000898992, ENST00000898993, ENST00000954018

RefSeq mRNA: 1 — MANE Select: NM_002122 NM_002122

CCDS: CCDS4752

Canonical transcript exons

ENST00000343139 — 5 exons

Exon	Start	End
ENSE00001521486	32642952	32643684
ENSE00001886858	32637406	32637540
ENSE00003527459	32641310	32641558
ENSE00003566368	32642610	32642784
ENSE00003658074	32641972	32642253

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 98.73.

FANTOM5 (CAGE): breadth broad, TPM avg 86.5165 / max 16107.0954, expressed in 571 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67161	78.7670	536
67162	4.5932	309
67143	0.9554	251
67142	0.8363	256
67167	0.5792	171
67144	0.2745	130
67145	0.1437	78
67165	0.1335	72
67168	0.0913	44
67164	0.0857	50

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gall bladder	UBERON:0002110	98.73	gold quality
rectum	UBERON:0001052	98.06	gold quality
monocyte	CL:0000576	97.86	gold quality
leukocyte	CL:0000738	97.75	gold quality
mononuclear cell	CL:0000842	97.71	gold quality
granulocyte	CL:0000094	97.67	gold quality
right lung	UBERON:0002167	97.40	gold quality
visceral pleura	UBERON:0002401	96.93	gold quality
spleen	UBERON:0002106	96.57	gold quality
decidua	UBERON:0002450	96.46	gold quality
lymph node	UBERON:0000029	96.37	gold quality
skin of hip	UBERON:0001554	96.11	gold quality
upper lobe of left lung	UBERON:0008952	96.02	gold quality
vermiform appendix	UBERON:0001154	95.10	gold quality
right coronary artery	UBERON:0001625	95.03	gold quality
upper lobe of lung	UBERON:0008948	94.45	gold quality
pleura	UBERON:0000977	94.21	gold quality
periodontal ligament	UBERON:0008266	93.52	gold quality
descending thoracic aorta	UBERON:0002345	93.02	gold quality
parietal pleura	UBERON:0002400	92.87	gold quality
tonsil	UBERON:0002372	90.93	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.87	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.43	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.06	gold quality
tibial nerve	UBERON:0001323	90.03	gold quality
calcaneal tendon	UBERON:0003701	90.00	gold quality
smooth muscle tissue	UBERON:0001135	89.55	gold quality
caecum	UBERON:0001153	89.25	gold quality
small intestine	UBERON:0002108	88.87	gold quality
skin of leg	UBERON:0001511	88.79	gold quality

Single-cell (SCXA)

Detected in 27 experiment(s), a significant marker in 26.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	6365.35
E-GEOD-135922	yes	4162.81
E-MTAB-8322	yes	4156.79
E-HCAD-15	yes	3592.52
E-MTAB-8495	yes	2962.76
E-GEOD-130148	yes	2703.58
E-HCAD-36	yes	2687.95
E-CURD-79	yes	2604.27
E-MTAB-10553	yes	2582.95
E-CURD-120	yes	2566.70
E-CURD-55	yes	2213.21
E-GEOD-139324	yes	2146.23
E-MTAB-8410	yes	2036.91
E-CURD-122	yes	1924.00
E-MTAB-6701	yes	1842.15

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF, ILF3, NFAT5, RFX5, RFXANK, RFXAP, SP1, TFAP2A

miRNA regulators (miRDB)

58 targeting HLA-DQA1, 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-4282	99.99	75.36	6408
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-182-3P	99.57	67.57	825
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-3150B-3P	98.81	67.21	1728

Literature-anchored findings (GeneRIF, showing 18)

• support is provided for roles of the DQ genes and the DRB1 gene (or a gene in linkage disequilibrium with it) in determining susceptibility to type 1 diabetes (PMID:11841488)
• Relative and absolute HLA-DQA1-DQB1 linked risk for developing type I diabetes before 40 years of age in the Belgian population (PMID:11916169)
• Relationship between HLA-DQA1, -DQB1 genes polymorphism and susceptilibity to bronchial asthma among Northern Hans (PMID:11953202)
• Lack of evidence for association of HLA-DQA1 genes and gastric cancer carcinogenesis or H. pylori infection. (PMID:11972882)
• HLA-DRB1, DQB1, and DQA1 allele profile in Brazilian patients with type 1 diabetes mellitus. (PMID:12021129)
• The combination of several polymorphic amino acid residues in the DQalpha and DQbeta chains forms a domain structure pattern and is associated with insulin-dependent diabetes mellitus. (PMID:12021143)
• genotype influences the relative risk of type 1 diabetes conferred by dietary factors (PMID:12027934)
• HLA DQA1-DQB1 genotypes in Bedouin families with celiac disease. (PMID:12039527)
• high frequency of HLA-DRB1*1501-DQA1*0102-DQB1*0602 haplotype in paroxysmal nocturnal hemoglobinuria(PNH), including AA-PNH syndrome, and aplastic anemia (AA) patients. (PMID:12070003)
• The HLA-DQ-specific response to an exogenous food antigen (wheat gluten) that is demonstrated in transgenic knockout mice mimics the MHC class II-restricted gluten sensitivity aspect of human celiac disease. (PMID:12421937)
• There is an association of HLA-DQ genotype in autoantibody-negative and rapid-onset type 1 diabetes. (PMID:12453977)
• polymorphic in acute rejection development in liver transplantation (PMID:12493453)
• association between DQA1*0301 and APS II or III since this allele was otherwise not significantly associated with any of its component diseases except alopecia (PMID:12734793)
• The frequency of alleles at this gene locus were typed at the DNA level and the genetic polymorphism characterized for Basques from Navarre, Spain. (PMID:12823770)
• HLA-DQA1 alleles do not appear to play a role in the persistence of microchimerism in the peripheral blood or T lymphocytes of patients with selected autoimmune diseases or in healthy individuals. (PMID:13130476)
• A peptide derived from residues 65-79 of the alpha-chain HLA class II molecule DQA03011 competitively inhibits binding of cell cycle regulator p21 to proliferating cell nuclear antigen (PCNA), inhibits T cell proliferation and induces T cell apoptosis. (PMID:14607903)
• No evidence of polymorphism with severe retinopathy in younger Type 1 diabetic patients. (PMID:15019597)
• ALLELES OF THE HLA-DQA1 GENE HAVE BEEN SHOWN TO BE ASSOCIATED WITH DIABETES MELLITUS IN STUDIES FROM MANY GEOGRAPHIC LOCATIONS.(P.298) (PMID:15112906)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	mhc2daa	ENSDARG00000031745
danio_rerio	mhc2d8.37a2	ENSDARG00000070206
danio_rerio	mhc2d8.37a1	ENSDARG00000074816
danio_rerio	mhc2d8.46a	ENSDARG00000075932
danio_rerio	zmp:0000001006	ENSDARG00000090839
danio_rerio	zgc:123107	ENSDARG00000101675
danio_rerio	si:busm1-194e12.8	ENSDARG00000103702
danio_rerio	mhc2dga	ENSDARG00000103716
danio_rerio	mhc2dca	ENSDARG00000114601
danio_rerio	mhc2d8.35a1	ENSDARG00000116565

Paralogs (13): B2M (ENSG00000166710), HLA-DQB1 (ENSG00000179344), HLA-DRB1 (ENSG00000196126), HLA-DRB5 (ENSG00000198502), HLA-DOA (ENSG00000204252), HLA-DMA (ENSG00000204257), HLA-DRA (ENSG00000204287), 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, DQ alpha 1 chain — P01909 (reviewed: P01909)

Alternative names: DC-1 alpha chain, DC-alpha, HLA-DCA, MHC class II DQA1

All UniProt accessions (5): A0A173ADG5, E9PI37, E9PMV2, F6UB03, P01909

UniProt curated annotations — full annotation on UniProt →

Function. Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of this complex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.

Subunit / interactions. Heterodimer of an alpha and a beta subunit; also referred as MHC class II molecule. In the endoplasmic reticulum (ER) it forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases; leaving a small fragment termed CLIP on each MHC class II molecule. MHC class II molecule interacts with HLA_DM, and HLA_DO in B-cells, in order to release CLIP and facilitate the binding of antigenic peptides.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane. Golgi apparatus. trans-Golgi network membrane. Endosome membrane. Lysosome membrane.

Polymorphism. The following alleles of DQA1 are known: DQA101:01, DQA101:02, DQA101:03, DQA101:04, DQA101:05, DQA101:06, DQA101:07, DQA102:01, DQA103:01, DQA103:02, DQA103:03, DQA104:01, DQA104:02, DQA104:03, DQA104:04, DQA105:01, DQA105:02, DQA105:03, DQA105:04, DQA105:05, DQA105:06, DQA105:07, DQA105:08, DQA105:09, DQA106:01, DQA106:02. The sequence shown is that of DQA105:01. DQ2 (heterodimer of DQA105:01/DQB102:01) is associated with more than 90% of celiac disease patients. A minority displays DQ8 (heterodimer of DQA103/DQB103:02). DQ0602 (heterodimer of DQA101:02/DQB1*06:02) confers dominant protection against type 1 diabetes (T1D) and strong susceptibility to narcolepsy.

Similarity. Belongs to the MHC class II family.

RefSeq proteins (1): NP_002113* (*=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 (103 total): sequence variant 64, strand 15, sequence conflict 6, helix 3, region of interest 3, turn 3, glycosylation site 2, topological domain 2, signal peptide 1, chain 1, disulfide bond 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

28 structures.

PDB	Method	Resolution (Å)
1UVQ	X-RAY DIFFRACTION	1.8
6U3M	X-RAY DIFFRACTION	1.9
5KSA	X-RAY DIFFRACTION	2
6MFG	X-RAY DIFFRACTION	2
2NNA	X-RAY DIFFRACTION	2.1
8W84	X-RAY DIFFRACTION	2.1
5KSV	X-RAY DIFFRACTION	2.19
9EJG	X-RAY DIFFRACTION	2.2
1S9V	X-RAY DIFFRACTION	2.22
8W86	X-RAY DIFFRACTION	2.24
1JK8	X-RAY DIFFRACTION	2.4
6XP6	X-RAY DIFFRACTION	2.4
9EJH	X-RAY DIFFRACTION	2.45
6MFF	X-RAY DIFFRACTION	2.6
4OZF	X-RAY DIFFRACTION	2.7
5KSU	X-RAY DIFFRACTION	2.73
8W85	X-RAY DIFFRACTION	2.77
4OZH	X-RAY DIFFRACTION	2.8
6U3N	X-RAY DIFFRACTION	2.8
8W83	X-RAY DIFFRACTION	2.82
5KSB	X-RAY DIFFRACTION	2.9
4OZG	X-RAY DIFFRACTION	3
7SG0	X-RAY DIFFRACTION	3
7SG1	X-RAY DIFFRACTION	3.1
7SG2	X-RAY DIFFRACTION	3.1
8VSP	ELECTRON MICROSCOPY	3.12
4GG6	X-RAY DIFFRACTION	3.2
4OZI	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01909-F1	88.56	0.69

Antibody-complex structures (SAbDab): 5 — 6XP6, 8W83, 8W84, 8W85, 8W86

Functional residue map

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

Disulfide bonds (1): 132–188

Glycosylation sites (2): 143, 103

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: 494 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II, WALLACE_PROSTATE_CANCER_RACE_UP, MCLACHLAN_DENTAL_CARIES_UP, CCAWYNNGAAR_UNKNOWN, SWEET_KRAS_ONCOGENIC_SIGNATURE, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOCC_VACUOLAR_MEMBRANE, HSIAO_HOUSEKEEPING_GENES, KYNG_DNA_DAMAGE_DN, GAURNIER_PSMD4_TARGETS, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_ANTIGEN, GRAHAM_CML_QUIESCENT_VS_NORMAL_QUIESCENT_DN

GO Biological Process (9): adaptive immune response (GO:0002250), peptide antigen assembly with MHC class II protein complex (GO:0002503), immune response (GO:0006955), antigen processing and presentation of exogenous peptide antigen via MHC class II (GO:0019886), positive regulation of immune response (GO:0050778), positive regulation of T cell activation (GO:0050870), immune system process (GO:0002376), antigen processing and presentation of peptide or polysaccharide antigen via MHC class II (GO:0002504), 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), lysosome (GO:0005764), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), endosome membrane (GO:0010008)

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	4
cytoplasmic vesicle membrane	3
endomembrane system	3
immune response	2
antigen processing and presentation of peptide antigen via MHC class II	2
immune system process	2
organelle membrane	2
cytoplasm	2
intracellular membrane-bounded organelle	2
MHC class II protein complex assembly	1
peptide antigen assembly with MHC protein complex	1
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
T cell activation	1
regulation of T cell activation	1
positive regulation of lymphocyte activation	1
positive regulation of leukocyte cell-cell adhesion	1
biological_process	1
antigen processing and presentation	1
MHC protein complex binding	1
transmembrane signaling receptor activity	1
MHC class II protein binding	1
immune receptor activity	1
antigen binding	1
peptide binding	1
binding	1
Golgi apparatus	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
COPII-coated ER to Golgi transport vesicle	1
transport vesicle membrane	1
coated vesicle membrane	1
cellular anatomical structure	1
transport vesicle	1
endocytic vesicle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

29 interactions, top by confidence:

A	B	Type	Score
HLA-DQA1	HLA-DQB1	psi-mi:“MI:0915”(physical association)	0.860
HLA-DQB1	HLA-DQA1	psi-mi:“MI:0915”(physical association)	0.860
HLA-DQA1	HLA-DQB1	psi-mi:“MI:2364”(proximity)	0.860
HLA-DQA1	HLA-DQB1	psi-mi:“MI:0407”(direct interaction)	0.860
HLA-DQA1	HCRT	psi-mi:“MI:0915”(physical association)	0.560
HLA-DQA1	CD74	psi-mi:“MI:2364”(proximity)	0.540
HLA-DQA1	CD74	psi-mi:“MI:0915”(physical association)	0.540
HLA-DQA1	CDK7	psi-mi:“MI:0915”(physical association)	0.370
HLA-DQA1	IKBKG	psi-mi:“MI:0915”(physical association)	0.370
HLA-DQA1	TMEM223	psi-mi:“MI:0914”(association)	0.350
TNFRSF10A	SDCBP	psi-mi:“MI:0914”(association)	0.350
CD14	MAN2B1	psi-mi:“MI:0914”(association)	0.350
DEFB110	NME2P1	psi-mi:“MI:0914”(association)	0.350
CCL17	LRP5	psi-mi:“MI:0914”(association)	0.350
HCRT	PMPCB	psi-mi:“MI:0914”(association)	0.350
FKBP2	HLA-DQA1	psi-mi:“MI:0914”(association)	0.350
VWC2	HLA-DQA1	psi-mi:“MI:0914”(association)	0.350
HLA-DQA1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
	HLA-DQA1	psi-mi:“MI:0915”(physical association)	0.000
HLA-DQA1	RIF1	psi-mi:“MI:0915”(physical association)	0.000
HLA-DQA1	TLE1	psi-mi:“MI:0915”(physical association)	0.000
HLA-DQA1	UNC119	psi-mi:“MI:0915”(physical association)	0.000
HLA-DQA1	APLP1	psi-mi:“MI:0915”(physical association)	0.000
HLA-DQA1	SH3GL2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (167): ATP2B2 (Affinity Capture-MS), TMEM214 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS), ATP6V0A1 (Affinity Capture-MS), MYO19 (Affinity Capture-MS), SLC30A9 (Affinity Capture-MS), TMEM246 (Affinity Capture-MS), HLA-A (Affinity Capture-MS), CUX1 (Affinity Capture-MS), EFNB1 (Affinity Capture-MS), TMEM57 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), DDX19B (Affinity Capture-MS), SLC27A6 (Affinity Capture-MS), GALT (Affinity Capture-MS)

ESM2 similar proteins: A0A5B9, A6NDV4, A6QLK4, B1AWJ5, E9PTA2, O75051, O94759, P01850, P01851, P01852, P01857, P01859, P01860, P01861, P01869, P01870, P01906, P01909, P03987, P06333, P0DSE2, P0DTU4, P11364, P15151, P15981, P20759, P20762, P32506, P54900, Q1WIM1, Q1WIM3, Q3TMX7, Q6P767, Q6ZRP7, Q7TQ33, Q812F8, Q8N126, Q8NFZ8, Q8R143, Q8R464

Diamond homologs: A0A5B9, A0M8Q6, B9A064, P01834, P01835, P01836, P01837, P01838, P01839, P01840, P01841, P01843, P01844, P01845, P01846, P01847, P01850, P01851, P01852, P01855, P01857, P01859, P01860, P01861, P01862, P01863, P01864, P01865, P01867, P01868, P01869, P01870, P01876, P01877, P01906, P01909, P03984, P03987, P03988, P04221

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
MARCHF9	“down-regulates quantity by destabilization”	HLA-DQA1	ubiquitination
“RFX complex”	“up-regulates quantity by expression”	HLA-DQA1	“transcriptional regulation”

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — PLMESO.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	10
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

607 predictions. Top by Δscore:

Variant	Effect	Δscore
6:32637537:GTGG:G	donor_gain	1.0000
6:32637539:GG:G	donor_gain	1.0000
6:32637540:GG:G	donor_gain	1.0000
6:32637541:GT:G	donor_loss	1.0000
6:32637542:T:A	donor_loss	1.0000
6:32642044:T:TA	acceptor_gain	1.0000
6:32642249:CTGGG:C	donor_gain	1.0000
6:32642250:TGGGG:T	donor_loss	1.0000
6:32642251:GGG:G	donor_gain	1.0000
6:32642252:GG:G	donor_gain	1.0000
6:32642252:GGG:G	donor_gain	1.0000
6:32642253:GG:G	donor_gain	1.0000
6:32642253:GGTAA:G	donor_loss	1.0000
6:32642255:T:G	donor_loss	1.0000
6:32642608:A:AG	acceptor_gain	1.0000
6:32642609:G:GG	acceptor_gain	1.0000
6:32637541:G:GG	donor_gain	0.9900
6:32637544:AGTG:A	donor_loss	0.9900
6:32641272:T:TA	acceptor_gain	0.9900
6:32641287:T:A	acceptor_gain	0.9900
6:32641329:T:TA	acceptor_gain	0.9900
6:32641969:CAGAG:C	acceptor_loss	0.9900
6:32641970:A:AG	acceptor_gain	0.9900
6:32641970:A:T	acceptor_loss	0.9900
6:32641971:G:GA	acceptor_loss	0.9900
6:32641971:G:GG	acceptor_gain	0.9900
6:32641971:GA:G	acceptor_gain	0.9900
6:32642045:G:A	acceptor_gain	0.9900
6:32642065:T:TA	acceptor_gain	0.9900
6:32642250:TGGG:T	donor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000401500 (6:32646283 T>C), RS1000620461 (6:32645194 T>G), RS1000665512 (6:32646298 C>G,T), RS1001712383 (6:32647990 C>A,G), RS1001794426 (6:32645814 A>G), RS1001913563 (6:32653958 G>A), RS1001932899 (6:32650328 C>A), RS1002029436 (6:32654351 G>A), RS1002088498 (6:32640694 T>C), RS1002761579 (6:32636776 T>C), RS1002885613 (6:32645665 A>G), RS1004178065 (6:32644122 G>A), RS1004197339 (6:32646606 A>G), RS1004825662 (6:32643410 C>G), RS1004899156 (6:32641785 G>A)

Disease associations

OMIM: gene MIM:146880 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): breast ductal adenocarcinoma (MONDO:0005590)

Orphanet (0):

HPO phenotypes

54 total (30 of 54 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000789	Infertility
HP:0000823	Delayed puberty
HP:0000939	Osteoporosis
HP:0000964	Eczematoid dermatitis
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001271	Polyneuropathy
HP:0001426	Non-Mendelian inheritance
HP:0001508	Failure to thrive
HP:0001596	Alopecia
HP:0001824	Weight loss
HP:0001891	Iron deficiency anemia
HP:0001894	Thrombocytosis
HP:0001972	Macrocytic anemia
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002015	Dysphagia
HP:0002020	Gastroesophageal reflux
HP:0002027	Abdominal pain
HP:0002100	Recurrent aspiration pneumonia
HP:0002514	Cerebral calcification
HP:0002570	Steatorrhea
HP:0002608	Celiac disease
HP:0002665	Lymphoma
HP:0002720	Decreased circulating IgA concentration
HP:0002748	Rickets
HP:0002829	Arthralgia

GWAS associations

312 associations (top):

Study	Trait	p-value
GCST000048_1	Celiac disease	1.000000e-19
GCST000144_7	Systemic lupus erythematosus	3.000000e-21
GCST000217_1	Rheumatoid arthritis	1.000000e-09
GCST000225_3	Inflammatory bowel disease	1.000000e-08
GCST000311_1	Ulcerative colitis	1.000000e-16
GCST000433_2	Schizophrenia	7.000000e-08
GCST000612_35	Celiac disease	1.000000e-50
GCST000662_5	Vitiligo	7.000000e-19
GCST000906_2	Chronic lymphocytic leukemia	9.000000e-08
GCST000964_4	Ulcerative colitis	1.000000e-55
GCST000984_2	Idiopathic membranous nephropathy	8.000000e-93
GCST000996_24	Systemic lupus erythematosus	8.000000e-06
GCST001009_5	Nephropathy	2.000000e-26
GCST001043_1	Response to interferon beta therapy	4.000000e-10
GCST001156_1	Systemic sclerosis	1.000000e-11
GCST001474_7	Hypothyroidism	5.000000e-07
GCST001547_7	Immune response to anthrax vaccine	6.000000e-06
GCST001603_1	Hepatocellular carcinoma	5.000000e-22
GCST001728_3	Ulcerative colitis	5.000000e-133
GCST001757_10	Schizophrenia	5.000000e-06
GCST001763_1	Asthma	2.000000e-08
GCST001785_9	Crohn’s disease	9.000000e-59
GCST001805_1	Leishmaniasis (visceral)	3.000000e-17
GCST001826_10	Lymphoma	2.000000e-08
GCST001826_2	Lymphoma	3.000000e-12
GCST001826_9	Lymphoma	3.000000e-06
GCST001892_6	Multiple sclerosis (OCB status)	2.000000e-20
GCST001900_4	Cervical cancer	3.000000e-22
GCST001938_2	Ulcerative colitis	1.000000e-18
GCST001942_21	Prostate cancer	5.000000e-09

EFO canonical traits (62, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0005206	oligoclonal band measurement
EFO:0005298	allergic sensitization measurement
EFO:0006929	IgG index
EFO:0007017	peanut allergy measurement
EFO:0007790	Epstein Barr virus nuclear antigen 1 IgG measurement
EFO:0007904	susceptibility to childhood ear infection measurement
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007994	neutrophil percentage of granulocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:1000965	Henoch-Schoenlein purpura
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0004340	body mass index
EFO:0007796	parental longevity
EFO:0008401	susceptibility to shingles measurement
EFO:0008406	susceptibility to plantar warts measurement
EFO:0008407	susceptibility to Mycobacterium tuberculosis infection measurement
EFO:0008409	susceptibility to scarlet fever measurement
EFO:0008410	susceptibility to pneumonia measurement
EFO:0007924	tonsillectomy risk measurement
EFO:0009180	rosacea severity measurement
EFO:0006941	grip strength measurement
EFO:0009271	Epstein Barr virus nuclear antigen-1 seropositivity
EFO:0004570	bilirubin measurement
EFO:0004587	lymphocyte count
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004695	intraocular pressure measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105884 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

5 annotations.

Variant	Type	Level	Drugs	Phenotypes
HLA-DQA1*01:03	Toxicity	3	Antithyroid Preparations	Agranulocytosis;Graves Disease
HLA-DQA1*02:01	Toxicity	3	azathioprine;mercaptopurine	Drug Toxicity;Inflammatory Bowel Diseases;Pancreatitis
HLA-DQA1*02:01	Toxicity	3	lapatinib	Toxic liver disease
HLA-DQA1*05	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Inflammatory Bowel Diseases
rs9272105	Efficacy	3	interferon beta-1a;interferon beta-1b

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs9272105	HLA-DQA1	3	1.50	1	interferon beta-1a;interferon beta-1b

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects expression, increases abundance, increases methylation	3
Arsenicals	decreases expression, affects expression, increases abundance	2
Mercury	decreases expression	2
testosterone enanthate	affects expression	1
propionaldehyde	decreases expression	1
quercitrin	affects expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects expression	1
di-n-butylphosphoric acid	affects expression	1
lumiracoxib	affects response to substance	1
Capecitabine	decreases expression	1
Fluvastatin	affects expression	1
Acetaminophen	increases expression	1
Auranofin	increases response to substance	1
Azathioprine	affects response to substance	1
Benzene	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Calcitriol	decreases expression	1
Dexamethasone	increases expression	1
Palladium	affects response to substance	1
Silver	decreases expression	1
Dronabinol	increases expression	1
Tobacco Smoke Pollution	affects expression	1
Mercaptopurine	affects response to substance	1
Antirheumatic Agents	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL924139	Binding	Binding affinity to human recombinant HLA-DQ2 at pH 7.0	Structure-based design of alpha-amido aldehyde containing gluten peptide analogues as modulators of HLA-DQ2 and transglutaminase 2. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery