HLA-E

Summary

HLA-E (major histocompatibility complex, class I, E, HGNC:4962) is a protein-coding gene on chromosome 6p22.1, encoding HLA class I histocompatibility antigen, alpha chain E (P13747). Non-classical major histocompatibility class Ib molecule involved in immune self-nonself discrimination.

HLA-E belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. HLA-E binds a restricted subset of peptides derived from the leader peptides of other class I molecules. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail.

Source: NCBI Gene 3133 — RefSeq curated summary.

At a glance

• GWAS associations: 30
• Clinical variants (ClinVar): 12 total
• MANE Select transcript: NM_005516

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4962
Approved symbol	HLA-E
Name	major histocompatibility complex, class I, E
Location	6p22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000204592
Ensembl biotype	protein_coding
OMIM	143010
Entrez	3133

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 2 retained_intron

ENST00000376630, ENST00000484194, ENST00000493699, ENST00000896637, ENST00000896638, ENST00000896639, ENST00000896640, ENST00000896641, ENST00000896642, ENST00000896643, ENST00000959570

RefSeq mRNA: 1 — MANE Select: NM_005516 NM_005516

CCDS: CCDS34379

Canonical transcript exons

ENST00000376630 — 8 exons

Exon	Start	End
ENSE00001599023	30492541	30492583
ENSE00001602381	30489726	30489995
ENSE00001607565	30491537	30491653
ENSE00001678486	30491137	30491412
ENSE00001682692	30492404	30492436
ENSE00001706094	30492749	30494194
ENSE00001908560	30489509	30489595
ENSE00003632534	30490240	30490515

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 300.7298 / max 6534.4183, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66723	299.8291	1825
66724	0.6605	317
66727	0.2402	88

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	99.83	gold quality
right lung	UBERON:0002167	99.83	gold quality
granulocyte	CL:0000094	99.80	gold quality
upper lobe of left lung	UBERON:0008952	99.73	gold quality
monocyte	CL:0000576	99.71	gold quality
leukocyte	CL:0000738	99.71	gold quality
spleen	UBERON:0002106	99.67	gold quality
lymph node	UBERON:0000029	99.62	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.58	gold quality
adipose tissue	UBERON:0001013	99.53	gold quality
vermiform appendix	UBERON:0001154	99.53	gold quality
gall bladder	UBERON:0002110	99.51	gold quality
thoracic mammary gland	UBERON:0005200	99.47	gold quality
omental fat pad	UBERON:0010414	99.47	gold quality
placenta	UBERON:0001987	99.44	gold quality
skin of abdomen	UBERON:0001416	99.42	gold quality
zone of skin	UBERON:0000014	99.41	gold quality
skin of leg	UBERON:0001511	99.41	gold quality
mucosa of stomach	UBERON:0001199	99.40	gold quality
calcaneal tendon	UBERON:0003701	99.40	gold quality
bone marrow	UBERON:0002371	99.39	gold quality
left lobe of thyroid gland	UBERON:0001120	99.37	gold quality
tibial nerve	UBERON:0001323	99.37	gold quality
endocervix	UBERON:0000458	99.36	gold quality
left uterine tube	UBERON:0001303	99.36	gold quality
thyroid gland	UBERON:0002046	99.36	gold quality
right lobe of thyroid gland	UBERON:0001119	99.35	gold quality
myometrium	UBERON:0001296	99.35	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.35	gold quality
fallopian tube	UBERON:0003889	99.33	gold quality

Single-cell (SCXA)

Detected in 29 experiment(s), a significant marker in 20.

Experiment	Marker?	Max mean expression
E-CURD-126	yes	7067.28
E-GEOD-124263	yes	815.56
E-MTAB-7051	yes	476.09
E-HCAD-6	yes	334.00
E-HCAD-1	yes	119.32
E-MTAB-10287	yes	95.36
E-GEOD-134144	yes	54.11
E-MTAB-8142	yes	43.98
E-MTAB-6701	yes	42.40
E-MTAB-8410	yes	31.86
E-HCAD-10	yes	25.77
E-HCAD-35	yes	25.19
E-MTAB-9221	yes	24.13
E-HCAD-9	yes	18.48
E-MTAB-7316	yes	14.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ATF1, BMAL1, CEBPB, CIITA, CREB1, CTCF, EZH2, FOS, FOXC1, FOXP3, GATA1, GATA6, GLI2, GLI3, HAND1, HAND2, HIVEP2, HLF, IRF1, IRF2, IRF4, IRF6, KMT2A, LHX2, MEF2A, MYC, MYCN, MYOD1, NFKB1, NFKB2, NFKB, NFX1, NFYA, NFYB, NR2E3, PAX1, PHF20, POU3F2, PPARA

miRNA regulators (miRDB)

34 targeting HLA-E, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-7114-5P	98.51	67.87	1349
HSA-MIR-211-3P	98.14	66.77	1052
HSA-MIR-12120	98.05	68.44	1768
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-1912-5P	97.94	67.98	832
HSA-MIR-379-5P	97.52	67.81	485
HSA-MIR-216B-5P	97.16	66.76	1126
HSA-MIR-3529-5P	97.12	67.06	440

Literature-anchored findings (GeneRIF, showing 40)

• Peptide binding specificity of HLA-E. (PMID:11432755)
• Signal peptide processing by signal peptidase is essential in the generation of HLA-E-binding epitopes derived from the signal sequence of polymorphic MHC class I molecules. (PMID:11714810)
• Soluble HLA-E tetramers refolded with different peptides (specifically stained K14 cells. HLA-E tetramer binding was reduced by pretreatment with anti-CD94 mAb alone, but was completely prevented in combination with anti-clonotypic mAb. (PMID:11920559)
• expresssion modulates cytokine production of monocyte generated dendritic cells (PMID:12232815)
• HLA-E allelic variants: differential expression, peptide affinities, crystal structures, and thermal stabilities. (PMID:12411439)
• HLA-E can present a peptide derived from the signal sequence of human hsp60. (PMID:12461076)
• Recognition of mycobacterium tuberculosis- derived antigen being presented in the context of HLA-E. (PMID:12461082)
• Expression was detected in tumor cell lines showing an imbalance in heavy chain/beta(2)m expression, particularly in tumor cell lines with alterations in the expression of heavy-chain genes. (PMID:12618909)
• HLA-E has been found in all cells of the placenta that express either the membrane-bound or soluble form of HLA-G, consistent with HLA-E being complexed with the HLA-G signal sequence-derived nonamer in these cells. (PMID:12874228)
• Results suggest that the GATA-1 transcription factor represents a cell type-restricted mediator of interferon-gamma induction of the HLA-E gene. (PMID:15226423)
• The presence of the appropriate HLA class I alleles with leader sequence-derived peptides and HLA-E heavy chain may not be sufficient to allow HLA-E surface expression in tumor cell lines as opposed to lymphoid cells. (PMID:15620456)
• the T cell epitope HCV core 35-44 stabilizes HLA-A2 and HLA-E and inhibits cytolysis mediated by natural killer cells (PMID:15681828)
• up-regulation of HLA-E expression and reduced susceptibility to NK cell cytotoxicity in HIV-1 infection (PMID:15751767)
• An HLA-E single chain trimer inhibits human NK cell reactivity towards porcine cells. (PMID:15829309)
• Data show that short tandem repeat of exon 5 of MHC class-I chain related gene A and association with nasopharyngeal carcinoma in a southern Chinese population. (PMID:15952123)
• Potential role of human leukocyte antigen (HLA)-E polymorphism on the incidence of early infections in patients identicslly matched for class I and Ii antigens. (PMID:16003246)
• Generation of an inhibitory HLA-E epitope derived from multidrug resistance-associated protein 7 (MRP-7) provides insight into the immunoregulatory role of HLA-E during cell stress. (PMID:16034073)
• HLA-E-restricted cytotoxic T-lymphocytes (CTL) may represent an additional effector cell type involved in defenses against human cytomegalovirus, a virus which escapes the control exerted by conventional CTL or natural killer (NK) cells. (PMID:16224817)
• The results of this analysis confirmed several previously reported coding sequence variants, identified several new allelic variants, and also defined extensive variation in intron and flanking sequences. (PMID:16570139)
• HLA-E expression and shedding are normal features of melanocytes, which are conserved in melanoma cells of primary tumors, but become dependent on IFN-gamma induction after metastasis (PMID:16920947)
• strong positive directional selection is acting for maintaining the observed low polymorphism on HLA-E, -F and -G loci (PMID:17157219)
• The homozygous state for HLA-E*0103 allele behaves as a protective genetic factor against acute graft versus host disease and transplant-related mortality. (PMID:17164714)
• Variant HLA-E and HLA-G molecules appear to function independently and synergistically, increasing the risk of Behcet’s disease. (PMID:17257316)
• indicate that the SNPs of the inhibitory receptor CD94/NKG2A and its haplotypes, as well as its ligand HLA-E, are associated with Behcet’s disease immune systems (PMID:17767552)
• summary of the current knowledge on HLA-E and HLA-G expression, regulation and functional relevance in various malignancies [review] (PMID:17768067)
• The decreased expression of HLA-G and HLA-E may play a role in the pathogenesis of intrahepatic cholestasis of pregnancy. (PMID:17953356)
• A bi-allelic polymorphism (Arg107Gly) of human leukocyte antigen-E (HLA-E) locus was investigated in sickle cell anemia patients originating from sub-Saharan Africa. HLA-E*0101/E*0101 genotype was more frequent among the group with severe infections. (PMID:17961774)
• the invariant CD94 chain plays a more dominant role in interacting with HLA-E in comparison to the variable NKG2 chain. (PMID:18083576)
• An extensive substitution analysis throughout the entire region of HLA-E led to the identification of nine amino acid positions that are significantly involved in the cell surface expression of HLA-E molecules. (PMID:18270229)
• Upregulation of HLA-E could be a marker of shorter disease-free survival in Dukes’ C patients. (PMID:18292941)
• crystal structure of CD94-NKG2A in complex with HLA-E bound to a peptide derived from the leader sequence of HLA-G (PMID:18332182)
• The evolution of the NKG2x/CD94 family of receptors has likely been shaped both by the need to bind the invariant HLA-E ligand and the need to avoid subversion by pathogen-derived decoys. (PMID:18448674)
• HLA-E overexpression seemed to be associated with invasive cervical cancer and HPV16/18 infection. (PMID:18692948)
• HLA-E (as an inhibitory ligand) expression influences the susceptibility of leukemic cells to the cytolytic activities of cytokine/TKD-activated NK cells. (PMID:18759005)
• findings show HLA-E is a good, and not a poor, beta(2)microglobulin assembler, and TAP/tapasin-assisted ligand donation is only one, and possibly not even the major, pathway leading to its stabilization and surface expression (PMID:18832701)
• The differential expression of HLA-E and PSG1 in the sperm of fertile and infertile men is discussed. (PMID:18987160)
• this is the first description of population frequencies of nine different SNPs in HLA-E in three main large ethnic groups (PMID:19140831)
• Our results suggest that the HLA-E gene polymorphism may play a role in the pathogenesis of Kawasaki Disease. (PMID:19180512)
• These results suggest that progesterone up-regulates HLA-E expression in JEG-3 cells through the pathway mediated by progesterone receptor. (PMID:19239424)
• The expressions of HLA-G and -E mRNA in the spontaneous abortion group were much lower than those in the control group. (PMID:19253840)

Cross-species orthologs

3 orthologs

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

Paralogs (22): HFE (ENSG00000010704), FCGRT (ENSG00000104870), ULBP1 (ENSG00000111981), ULBP2 (ENSG00000131015), ULBP3 (ENSG00000131019), MR1 (ENSG00000153029), RAET1L (ENSG00000155918), CD1D (ENSG00000158473), CD1A (ENSG00000158477), CD1C (ENSG00000158481), CD1B (ENSG00000158485), CD1E (ENSG00000158488), AZGP1 (ENSG00000160862), RAET1E (ENSG00000164520), RAET1G (ENSG00000203722), MICB (ENSG00000204516), MICA (ENSG00000204520), HLA-C (ENSG00000204525), HLA-G (ENSG00000204632), HLA-F (ENSG00000204642), HLA-A (ENSG00000206503), HLA-B (ENSG00000234745)

Protein

Protein identifiers

HLA class I histocompatibility antigen, alpha chain E — P13747 (reviewed: P13747)

Alternative names: MHC class I antigen E

All UniProt accessions (3): A0A4E9D3W4, P13747, Q2L6I5

UniProt curated annotations — full annotation on UniProt →

Function. Non-classical major histocompatibility class Ib molecule involved in immune self-nonself discrimination. In complex with B2M/beta-2-microglobulin binds nonamer self-peptides derived from the signal sequence of classical MHC class Ia molecules (VL9 peptides - VMAPRT[V/L][L/V/I/F]L). Peptide-bound HLA-E-B2M heterotrimeric complex primarily functions as a ligand for natural killer (NK) cell inhibitory receptor KLRD1-KLRC1, enabling NK cells to monitor the expression of other MHC class I molecules in healthy cells and to tolerate self. Upon cellular stress, preferentially binds signal sequence-derived peptides from stress-induced chaperones and is no longer recognized by NK cell inhibitory receptor KLRD1-KLRC1, resulting in impaired protection from NK cells. Binds signal sequence-derived peptides from non-classical MHC class Ib HLA-G molecules and acts as a ligand for NK cell activating receptor KLRD1-KLRC2, likely playing a role in the generation and effector functions of adaptive NK cells and in maternal-fetal tolerance during pregnancy. Besides self-peptides, can also bind and present pathogen-derived peptides conformationally similar to VL9 peptides to alpha-beta T cell receptor (TCR) on unconventional CD8-positive cytotoxic T cells, ultimately triggering antimicrobial immune response. Presents HIV gag peptides (immunodominant KAFSPEVIPMF and subdominant KALGPAATL epitopes) predominantly to CD8-positive T cell clones expressing a TRAV17-containing TCR, triggering HLA-E-restricted T cell responses. Presents mycobacterial peptides to HLA-E-restricted CD8-positive T cells eliciting both cytotoxic and immunoregulatory functions. (Microbial infection) Viruses like human cytomegalovirus have evolved an escape mechanism whereby virus-induced down-regulation of host MHC class I molecules is coupled to the binding of viral peptides to HLA-E, restoring HLA-E expression and inducing HLA-E-dependent NK cell immune tolerance to infected cells. (Microbial infection) May bind HIV-1 gag/Capsid protein p24-derived peptide (AISPRTLNA) on infected cells and may inhibit NK cell cytotoxicity, a mechanism that allows HIV-1 to escape immune recognition. (Microbial infection) Upon SARS-CoV-2 infection, may contribute to functional exhaustion of cytotoxic NK cells and CD8-positive T cells. Binds SARS-CoV-2 S/Spike protein S1-derived peptide (LQPRTFLL) expressed on the surface of lung epithelial cells, inducing NK cell exhaustion and dampening of antiviral immune surveillance.

Subunit / interactions. Forms a heterotrimer with B2M and a self- or a pathogen-derived peptide (peptide-bound HLA-E-B2M). Similarly to MHC class Ia assembly, HLA-E-B2M heterodimer interacts with components of the antigen processing machinery TAPBP and TAP1-TAP2 complex; this interaction is required for peptide loading and translocation to the cell surface. Interacts with CALCR; this interaction is required for appropriate folding. The optimum binding peptide is a nonamer (VL9) that is primarily derived from amino-acid residues 3-11 of the signal sequences of most HLA-A, -B, -C and -G molecules. The VL9 peptide anchors to five main sites in the peptide-binding groove of HLA-E. Peptide-bound HLA-E-B2M complex interacts with KLRD1-KLRC1 receptor on NK cells. Binds with lower affinity to activating KLRD1-KLRC2. The common subunit KLRC1 plays a prominent role in directly interacting with HLA-E. Peptide-bound HLA-E-B2M interacts with the alpha-beta TCR on unconventional CD8+ T cells. Peptide-free HLA-E interacts with HLA-F-B2M complex; this interaction may regulate the intracellular trafficking and the stability of peptide-free MHC class I open conformers (OCs).

Subcellular location. Cell membrane. Golgi apparatus membrane Secreted.

Tissue specificity. Expressed in secretory endometrial cells during pregnancy (at protein level). The expression in nonlymphoid tissues is restricted to endothelial cells from all types of vessels, including arteries, veins, capillaries, and lymphatics (at protein level). In lymphoid organs, it is mainly expressed in endothelial venules, B and T cells, monocytes, macrophages, NK cells and megakaryocytes (at protein level).

Post-translational modifications. N-glycosylated. The soluble form (sHLA-E) can be partly produced by proteolytic cleavage at the cell surface (shedding) by a matrix metalloproteinase. Alternative splicing is also suggested as a mechanism for generation of sHLA-E, although it remains to be proved.

Induction. Pro-inflammatory cytokines including TNF, IL1B and IFNG up-regulate membrane bound HLA-E expression on endothelial and NK cells and induce the release of soluble HLA-E (sHLA-E) in the extracellular compartment.

Polymorphism. The following alleles are known: E01:01 and E01:03. The frequency of E01:01 and E01:03 alleles in the population is about equal suggesting balanced selection in diverse populations. Evolutionary studies suggest that E01:03 is the original allele. Two other alleles has been described E01:02 and E01:04. Allele E01:02 was found to be identical to HLA E01:01. The existence of allele E01:04 is uncertain as it could not be confirmed in further studies. The sequence shown is that of E*01:03.

Similarity. Belongs to the MHC class I family.

RefSeq proteins (1): NP_005507* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001039	MHC_I_a_a1/a2	Domain
IPR003006	Ig/MHC_CS	Conserved_site
IPR003597	Ig_C1-set	Domain
IPR007110	Ig-like_dom	Domain
IPR010579	MHC_I_a_C	Domain
IPR011161	MHC_I-like_Ag-recog	Domain
IPR011162	MHC_I/II-like_Ag-recog	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR037055	MHC_I-like_Ag-recog_sf	Homologous_superfamily
IPR050208	MHC_class-I_related	Family

Pfam: PF00129, PF06623, PF07654

UniProt features (83 total): strand 21, mutagenesis site 17, binding site 16, helix 7, region of interest 5, sequence variant 3, chain 2, topological domain 2, disulfide bond 2, sequence conflict 2, signal peptide 1, compositionally biased region 1, modified residue 1, glycosylation site 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

34 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7P4B	X-RAY DIFFRACTION	1.72
7BH8	X-RAY DIFFRACTION	1.8
7P49	X-RAY DIFFRACTION	2.05
6GH1	X-RAY DIFFRACTION	2.1
9NW7	X-RAY DIFFRACTION	2.1
6GH4	X-RAY DIFFRACTION	2.16
6ZKX	X-RAY DIFFRACTION	2.17
8RLT	X-RAY DIFFRACTION	2.25
6ZKW	X-RAY DIFFRACTION	2.26
6ZKZ	X-RAY DIFFRACTION	2.3
9NW8	X-RAY DIFFRACTION	2.3
9NW9	X-RAY DIFFRACTION	2.3
8QFY	X-RAY DIFFRACTION	2.33
8RLU	X-RAY DIFFRACTION	2.35
3BZE	X-RAY DIFFRACTION	2.5
3BZF	X-RAY DIFFRACTION	2.5
6GHN	X-RAY DIFFRACTION	2.54
7NDQ	X-RAY DIFFRACTION	2.55
2ESV	X-RAY DIFFRACTION	2.6
8RLV	X-RAY DIFFRACTION	2.61
6GL1	X-RAY DIFFRACTION	2.62
6ZKY	X-RAY DIFFRACTION	2.65
6GGM	X-RAY DIFFRACTION	2.73
1KPR	X-RAY DIFFRACTION	2.8
3AM8	X-RAY DIFFRACTION	2.8
1MHE	X-RAY DIFFRACTION	2.85
7NDU	X-RAY DIFFRACTION	2.9
7NDT	X-RAY DIFFRACTION	3
1KTL	X-RAY DIFFRACTION	3.1
5W1W	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13747-F1	87.97	0.77

Antibody-complex structures (SAbDab): 1 — 7BH8

Functional residue map

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

Ligand- & substrate-binding residues (16): 28; 84; 87; 98; 98; 105; 105; 164; 164; 167; 167; 177 …

Post-translational modifications (1): 353

Disulfide bonds (2): 122–185, 224–280

Glycosylation sites (1): 107

Mutagenesis-validated functional residues (17):

Position	Phenotype
83	has no impact on the affinity for klrd1-klrc1.
86	reduces the affinity for klrd1-klrc1.
90	has no impact on the affinity for klrd1-klrc1.
93	impairs the recognition by klrd1-klrc1.
96	abolishes the recognition by klrd1-klrc1.
97	impairs the recognition by klrd1-klrc1.
100	reduces the affinity for klrd1-klrc1.
110	has no impact on the affinity for klrd1-klrc1.
129	has no impact on the affinity for klrd1-klrc1.
167	impairs folding.
170	has no impact on the affinity for klrd1-klrc1.
173	impairs the recognition by klrd1-klrc1.
175	has no impact on the affinity for klrd1-klrc1.
176	has no impact on the affinity for klrd1-klrc1.
183	impairs the recognition by klrd1-klrc1.
187	reduces the affinity for klrd1-klrc1.
235	has no impact on the affinity for klrd1-klrc1.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-1236974	ER-Phagosome pathway
R-HSA-1236977	Endosomal/Vacuolar pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-2172127	DAP12 interactions
R-HSA-2424491	DAP12 signaling
R-HSA-877300	Interferon gamma signaling
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-983170	Antigen Presentation: Folding, assembly and peptide loading of class I MHC

MSigDB gene sets: 543 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_TOLERANCE_INDUCTION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, REACTOME_ANTIGEN_PRESENTATION_FOLDING_ASSEMBLY_AND_PEPTIDE_LOADING_OF_CLASS_I_MHC, BASSO_B_LYMPHOCYTE_NETWORK, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION

GO Biological Process (34): positive regulation of antibody-dependent cellular cytotoxicity (GO:0001815), positive regulation of T cell mediated cytotoxicity (GO:0001916), adaptive immune response (GO:0002250), antigen processing and presentation of endogenous peptide antigen via MHC class Ib (GO:0002476), antigen processing and presentation of exogenous peptide antigen via MHC class Ib (GO:0002477), antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent (GO:0002486), natural killer cell tolerance induction (GO:0002519), positive regulation of immunoglobulin production (GO:0002639), regulation of natural killer cell mediated immunity (GO:0002715), positive regulation of natural killer cell mediated immunity (GO:0002717), positive regulation of natural killer cell cytokine production (GO:0002729), immune response (GO:0006955), antibacterial humoral response (GO:0019731), positive regulation of interleukin-13 production (GO:0032736), positive regulation of interleukin-4 production (GO:0032753), positive regulation of TRAIL production (GO:0032759), positive regulation of tumor necrosis factor production (GO:0032760), negative regulation of natural killer cell activation (GO:0032815), positive regulation of natural killer cell activation (GO:0032816), positive regulation of natural killer cell proliferation (GO:0032819), CD8-positive, alpha-beta T cell activation (GO:0036037), negative regulation of T cell proliferation (GO:0042130), protection from natural killer cell mediated cytotoxicity (GO:0042270), innate immune response (GO:0045087), negative regulation of natural killer cell mediated cytotoxicity (GO:0045953), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954), defense response to Gram-positive bacterium (GO:0050830), positive regulation of CD8-positive, alpha-beta T cell proliferation (GO:2000566), positive regulation of CD8-positive, alpha-beta T cell activation (GO:2001187), natural killer cell mediated immunity (GO:0002228), immune system process (GO:0002376), antigen processing and presentation of peptide antigen via MHC class I (GO:0002474), signal transduction (GO:0007165), antigen processing and presentation (GO:0019882)

GO Molecular Function (8): signaling receptor binding (GO:0005102), beta-2-microglobulin binding (GO:0030881), MHC class I protein binding (GO:0042288), peptide antigen binding (GO:0042605), T cell receptor binding (GO:0042608), natural killer cell lectin-like receptor binding (GO:0046703), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (16): Golgi membrane (GO:0000139), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), ER to Golgi transport vesicle membrane (GO:0012507), phagocytic vesicle membrane (GO:0030670), early endosome membrane (GO:0031901), MHC class Ib protein complex (GO:0032398), MHC class I protein complex (GO:0042612), recycling endosome membrane (GO:0055038), extracellular exosome (GO:0070062), lumenal side of endoplasmic reticulum membrane (GO:0098553), extracellular region (GO:0005576), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Antigen processing-Cross presentation	2
Interferon Signaling	2
Adaptive Immune System	1
Innate Immune System	1
DAP12 interactions	1
SARS-CoV-2-host interactions	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signaling receptor binding	3
cellular anatomical structure	3
positive regulation of leukocyte mediated cytotoxicity	2
antigen processing and presentation of peptide antigen via MHC class Ib	2
natural killer cell mediated immunity	2
positive regulation of cytokine production	2
positive regulation of tumor necrosis factor superfamily cytokine production	2
natural killer cell activation	2
regulation of natural killer cell activation	2
protein binding	2
endosome membrane	2
MHC protein complex	2
antibody-dependent cellular cytotoxicity	1
positive regulation of type IIa hypersensitivity	1
regulation of antibody-dependent cellular cytotoxicity	1
T cell mediated cytotoxicity	1
regulation of T cell mediated cytotoxicity	1
positive regulation of T cell mediated immunity	1
immune response	1
antigen processing and presentation of endogenous peptide antigen	1
antigen processing and presentation of exogenous peptide antigen	1
antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway	1
tolerance induction	1
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune response	1
regulation of lymphocyte mediated immunity	1
regulation of innate immune response	1
positive regulation of lymphocyte mediated immunity	1
regulation of natural killer cell mediated immunity	1
positive regulation of innate immune response	1
natural killer cell cytokine production	1
positive regulation of natural killer cell mediated immunity	1
positive regulation of cytokine production involved in immune response	1
regulation of natural killer cell cytokine production	1
immune system process	1
response to stimulus	1
antimicrobial humoral response	1
defense response to bacterium	1
interleukin-13 production	1

Protein interactions and networks

STRING

1800 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HLA-E	KLRD1	Q13241	999
HLA-E	KLRC1	P26715	999
HLA-E	KLRC2	P26717	999
HLA-E	KLRK1	P26718	996
HLA-E	LILRB1	Q8NHL6	995
HLA-E	CD8A	P01732	986
HLA-E	KLRC3	Q07444	986
HLA-E	B2M	P01884	966
HLA-E	KIR2DL4	P78400	935
HLA-E	KIR2DL1	P43626	911
HLA-E	KLRB1	Q12918	883
HLA-E	NCR3	O14931	870
HLA-E	KIR3DL1	P43629	805
HLA-E	NCR2	O95944	792
HLA-E	CD226	Q15762	790

IntAct

70 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
HLA-C	HLA-A	psi-mi:“MI:0914”(association)	0.670
HLA-F	HLA-E	psi-mi:“MI:0915”(physical association)	0.660
HLA-F	HLA-E	psi-mi:“MI:0407”(direct interaction)	0.660
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
B2M	HLA-E	psi-mi:“MI:0915”(physical association)	0.590
B2M	TAPBP	psi-mi:“MI:0915”(physical association)	0.570
HLA-G	HLA-B	psi-mi:“MI:0914”(association)	0.530
ADAM21	PLXNA2	psi-mi:“MI:0914”(association)	0.530
HLA-B	LTN1	psi-mi:“MI:0914”(association)	0.530
PBXIP1	KCNN4	psi-mi:“MI:0914”(association)	0.530
KLRD1	HLA-E	psi-mi:“MI:0915”(physical association)	0.400
USP22	HLA-E	psi-mi:“MI:0915”(physical association)	0.400
HLA-E	F2RL1	psi-mi:“MI:0915”(physical association)	0.370
HLA-E	RTL8C	psi-mi:“MI:0914”(association)	0.350
HLA-B		psi-mi:“MI:0914”(association)	0.350
NS3	C15orf61	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
TMEM106A	QSOX1	psi-mi:“MI:0914”(association)	0.350
HLA-E	ECEL1	psi-mi:“MI:0914”(association)	0.350
HLA-C	HLA-H	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

BioGRID (152): HLA-E (Affinity Capture-MS), HLA-E (Affinity Capture-MS), ATF6 (Affinity Capture-MS), TCTN2 (Affinity Capture-MS), HLA-F (Affinity Capture-MS), HLA-A (Affinity Capture-MS), HLA-H (Affinity Capture-MS), NDST2 (Affinity Capture-MS), NDST1 (Affinity Capture-MS), FAM127A (Affinity Capture-MS), METTL13 (Affinity Capture-MS), ASPH (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), HLA-DPB1 (Affinity Capture-MS), PLXNA3 (Affinity Capture-MS)

ESM2 similar proteins: C1ITJ8, O19477, O35799, P01899, P01901, P01902, P01920, P01921, P03991, P04440, P05538, P06339, P06342, P06345, P13747, P14427, P14428, P14429, P14432, P14483, P15464, P15979, P15982, P15983, P16212, P16391, P18470, P25311, P29826, P30383, P30517, P60018, P70387, Q29980, Q29983, Q2KN22, Q30201, Q3ZCH5, Q5RD09, Q63678

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

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CIITA	“up-regulates quantity by expression”	HLA-E	“transcriptional regulation”
MYC	“down-regulates quantity by repression”	HLA-E	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 65 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
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	7	81.1×	1e-10
ER-Phagosome pathway	7	26.7×	2e-07
Interferon gamma signaling	7	25.8×	2e-07
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	9	23.1×	5e-09
Interferon alpha/beta signaling	5	22.4×	5e-05
SARS-CoV-2 activates/modulates innate and adaptive immune responses	6	15.7×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of T cell mediated cytotoxicity	7	76.1×	1e-09
immune response	8	8.0×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

1126 predictions. Top by Δscore:

Variant	Effect	Δscore
6:30490493:G:GT	donor_gain	1.0000
6:30490493:G:T	donor_gain	1.0000
6:30490511:CCTGG:C	donor_gain	1.0000
6:30490512:CTGGG:C	donor_loss	1.0000
6:30490513:TGGGT:T	donor_loss	1.0000
6:30490514:GG:G	donor_gain	1.0000
6:30490515:GG:G	donor_gain	1.0000
6:30490515:GGTA:G	donor_loss	1.0000
6:30490516:G:A	donor_loss	1.0000
6:30490516:G:GG	donor_gain	1.0000
6:30490517:T:A	donor_loss	1.0000
6:30491410:G:GT	donor_gain	1.0000
6:30491413:G:GG	donor_gain	1.0000
6:30491640:G:GT	donor_gain	1.0000
6:30492536:CCCAG:C	acceptor_loss	1.0000
6:30492537:CCAGG:C	acceptor_loss	1.0000
6:30492539:A:AG	acceptor_gain	1.0000
6:30492539:AG:A	acceptor_gain	1.0000
6:30492540:G:GG	acceptor_gain	1.0000
6:30492540:G:T	acceptor_loss	1.0000
6:30492540:GG:G	acceptor_gain	1.0000
6:30492585:T:A	donor_loss	1.0000
6:30489991:GGCCG:G	donor_gain	0.9900
6:30489992:GCCG:G	donor_gain	0.9900
6:30489992:GCCGG:G	donor_gain	0.9900
6:30489996:G:GG	donor_gain	0.9900
6:30489996:GTGA:G	donor_loss	0.9900
6:30489997:TGA:T	donor_loss	0.9900
6:30489998:GAGTG:G	donor_loss	0.9900
6:30489999:AGTG:A	donor_loss	0.9900

AlphaMissense

2315 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:30491211:T:C	F229L	0.987
6:30491213:C:A	F229L	0.987
6:30491213:C:G	F229L	0.987
6:30491310:T:C	F262L	0.982
6:30491312:C:A	F262L	0.982
6:30491312:C:G	F262L	0.982
6:30489830:T:C	F57L	0.975
6:30489832:C:A	F57L	0.975
6:30489832:C:G	F57L	0.975
6:30491240:G:C	W238C	0.958
6:30491240:G:T	W238C	0.958
6:30491321:G:C	W265C	0.957
6:30491321:G:T	W265C	0.957
6:30489788:T:C	F43L	0.954
6:30489790:C:A	F43L	0.954
6:30489790:C:G	F43L	0.954
6:30491238:T:A	W238R	0.949
6:30491238:T:C	W238R	0.949
6:30489821:T:C	F54L	0.943
6:30489823:C:A	F54L	0.943
6:30489823:C:G	F54L	0.943
6:30489877:G:C	W72C	0.938
6:30489877:G:T	W72C	0.938
6:30491196:T:A	C224S	0.937
6:30491197:G:C	C224S	0.937
6:30491364:T:A	C280S	0.935
6:30491365:G:C	C280S	0.935
6:30491196:T:C	C224R	0.933
6:30491212:T:C	F229S	0.930
6:30490314:T:C	F137L	0.928

dbSNP variants (sampled 300 via entrez): RS1000413681 (6:30489388 T>A,C,G), RS1001937932 (6:30492442 T>G), RS1002392425 (6:30488364 A>C), RS1003808081 (6:30489870 C>G), RS1003909041 (6:30490398 G>A,C), RS1004881540 (6:30489748 C>A,G,T), RS1005881873 (6:30493105 A>G), RS1005891651 (6:30493253 G>A,T), RS1006664528 (6:30488492 C>A), RS1006734133 (6:30488042 G>A,T), RS1007134037 (6:30487678 C>A,T), RS1008153826 (6:30488242 T>C), RS1008206715 (6:30492160 T>C), RS1008543376 (6:30493949 T>C), RS1009064434 (6:30489275 G>A)

Disease associations

OMIM: gene MIM:143010 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

30 associations (top):

Study	Trait	p-value
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_121	Autism spectrum disorder or schizophrenia	3.000000e-13
GCST004521_132	Autism spectrum disorder or schizophrenia	2.000000e-09
GCST004521_171	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_2	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_210	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_263	Autism spectrum disorder or schizophrenia	7.000000e-17
GCST004521_265	Autism spectrum disorder or schizophrenia	7.000000e-14
GCST004521_269	Autism spectrum disorder or schizophrenia	7.000000e-11
GCST004521_295	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_3	Autism spectrum disorder or schizophrenia	2.000000e-15
GCST004521_56	Autism spectrum disorder or schizophrenia	1.000000e-22
GCST004521_70	Autism spectrum disorder or schizophrenia	8.000000e-20
GCST004521_79	Autism spectrum disorder or schizophrenia	1.000000e-16
GCST004746_4	Small cell lung carcinoma	4.000000e-06
GCST004748_101	Lung cancer	4.000000e-18
GCST004748_102	Lung cancer	2.000000e-18
GCST004749_85	Lung cancer in ever smokers	7.000000e-13
GCST004749_86	Lung cancer in ever smokers	1.000000e-12
GCST004750_51	Squamous cell lung carcinoma	3.000000e-14
GCST004750_52	Squamous cell lung carcinoma	5.000000e-14
GCST005232_23	Neuroticism	8.000000e-09
GCST005541_12	Sarcoidosis (Lofgren’s syndrome vs non-Lofgren’s syndrome)	4.000000e-23
GCST005790_54	Rosacea symptom severity	4.000000e-07
GCST005790_55	Rosacea symptom severity	2.000000e-06
GCST010083_8	Hemoglobin levels	4.000000e-11
GCST90002400_568	Plateletcrit	8.000000e-24
GCST90002403_387	Red blood cell count	3.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0009180	rosacea severity measurement
EFO:0004509	hemoglobin measurement
EFO:0007985	platelet crit
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1264457	Efficacy	3	adalimumab;certolizumab pegol;etanercept;glucocorticoids;infliximab;methotrexate	Rheumatoid arthritis

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1264457	HLA-E	3	2.00	1	adalimumab;certolizumab pegol;etanercept;glucocorticoids;infliximab;methotrexate

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
Arsenic Trioxide	increases expression, decreases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Testosterone	affects cotreatment, increases expression, decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	decreases expression, increases methylation	2
Tretinoin	increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
quercitrin	affects expression	1
beta-lapachone	increases expression	1
methylparaben	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
ochratoxin A	increases acetylation, increases expression	1
tamibarotene	increases expression	1
4-phenylbutyric acid	increases expression	1
corosolic acid	increases expression	1
entinostat	increases expression	1
K 7174	increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
MRK 003	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Antimycin A	increases expression	1
Cadmium	increases abundance, increases expression	1
Calcitriol	increases expression, affects cotreatment	1

Cellosaurus cell lines

9 cell lines: 7 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1FL	Abcam A-549 HLA-E KO 2	Cancer cell line	Male
CVCL_B2N4	Abcam A-549 HLA-E KO 1	Cancer cell line	Male
CVCL_B2YR	Abcam HEK293T HLA-E KO	Transformed cell line	Female
CVCL_E1Z4	HAP1 HLA-E (-) 2	Cancer cell line	Male
CVCL_E1Z5	HAP1 HLA-E (-) 3	Cancer cell line	Male
CVCL_E1Z6	HAP1 HLA-E (-) 4	Cancer cell line	Male
CVCL_E1Z7	HAP1 HLA-E (-) 5	Cancer cell line	Male
CVCL_E6U2	Genomeditech HEK-293 H_HLA-E	Transformed cell line	Female
CVCL_XP56	HAP1 HLA-E (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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