KLRD1

Summary

KLRD1 (killer cell lectin like receptor D1, HGNC:6378) is a protein-coding gene on chromosome 12p13.2, encoding Natural killer cells antigen CD94 (Q13241). Immune receptor involved in self-nonself discrimination.

Natural killer (NK) cells are a distinct lineage of lymphocytes that mediate cytotoxic activity and secrete cytokines upon immune stimulation. Several genes of the C-type lectin superfamily, including members of the NKG2 family, are expressed by NK cells and may be involved in the regulation of NK cell function. KLRD1 (CD94) is an antigen preferentially expressed on NK cells and is classified as a type II membrane protein because it has an external C terminus. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3824 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 26 total
• MANE Select transcript: NM_002262

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6378
Approved symbol	KLRD1
Name	killer cell lectin like receptor D1
Location	12p13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000134539
Ensembl biotype	protein_coding
OMIM	602894
Entrez	3824

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000336164, ENST00000344825, ENST00000350274, ENST00000381908, ENST00000538997, ENST00000539374, ENST00000539792, ENST00000540271, ENST00000543420, ENST00000543777, ENST00000544747, ENST00000862987

RefSeq mRNA: 8 — MANE Select: NM_002262 NM_001114396, NM_001351060, NM_001351062, NM_001351063, NM_001414224, NM_001414225, NM_002262, NM_007334

CCDS: CCDS8621, CCDS8622, CCDS86281

Canonical transcript exons

ENST00000336164 — 6 exons

Exon	Start	End
ENSE00003478520	10309626	10309688
ENSE00003537824	10313410	10313513
ENSE00003641739	10311464	10311615
ENSE00003847584	10307870	10308084
ENSE00003848453	10314673	10329608
ENSE00003888744	10309388	10309480

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 97.58.

FANTOM5 (CAGE): breadth broad, TPM avg 7.3081 / max 2174.7974, expressed in 202 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124159	6.2533	183
124161	0.5782	63
124160	0.4393	51
124162	0.0373	20

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.58	gold quality
buccal mucosa cell	CL:0002336	90.71	silver quality
blood	UBERON:0000178	89.14	gold quality
spleen	UBERON:0002106	86.87	gold quality
cervix squamous epithelium	UBERON:0006922	81.42	gold quality
bone marrow	UBERON:0002371	78.32	gold quality
lymph node	UBERON:0000029	77.63	gold quality
bone marrow cell	CL:0002092	77.29	gold quality
leukocyte	CL:0000738	76.28	gold quality
upper lobe of left lung	UBERON:0008952	74.84	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.74	gold quality
mononuclear cell	CL:0000842	74.27	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.26	gold quality
monocyte	CL:0000576	73.64	gold quality
upper lobe of lung	UBERON:0008948	73.08	gold quality
right lung	UBERON:0002167	72.65	gold quality
gall bladder	UBERON:0002110	72.37	gold quality
jejunal mucosa	UBERON:0000399	72.34	gold quality
vermiform appendix	UBERON:0001154	71.81	gold quality
adenohypophysis	UBERON:0002196	70.53	gold quality
omental fat pad	UBERON:0010414	69.99	gold quality
peritoneum	UBERON:0002358	69.91	gold quality
right lobe of liver	UBERON:0001114	69.66	gold quality
pituitary gland	UBERON:0000007	69.58	gold quality
adipose tissue of abdominal region	UBERON:0007808	69.16	gold quality
tongue squamous epithelium	UBERON:0006919	69.14	gold quality
colonic epithelium	UBERON:0000397	68.42	gold quality
small intestine Peyer’s patch	UBERON:0003454	68.30	gold quality
right coronary artery	UBERON:0001625	67.96	gold quality
hair follicle	UBERON:0002073	67.87	gold quality

Single-cell (SCXA)

Detected in 38 experiment(s), a significant marker in 36.

Experiment	Marker?	Max mean expression
E-GEOD-70580	yes	2834.59
E-CURD-46	yes	2143.55
E-MTAB-6653	yes	2103.54
E-MTAB-10553	yes	2011.77
E-MTAB-8530	yes	1742.73
E-HCAD-1	yes	1732.40
E-MTAB-6678	yes	1667.59
E-CURD-88	yes	1641.05
E-HCAD-15	yes	1471.32
E-MTAB-8410	yes	1463.97
E-MTAB-6701	yes	1385.94
E-HCAD-9	yes	1362.53
E-GEOD-139324	yes	1289.36
E-GEOD-150728	yes	1246.82
E-GEOD-149689	yes	1241.79

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

123 targeting KLRD1, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• Conservation and variation in human and chimpanzee CD94 genes (PMID:11751968)
• A critical role of CD94-dependent MHC-I recognition for the regulation of IFN-gamma production and target lysis was demonstrated. (PMID:12149421)
• Role that each NKG2A immunoreceptor tyrosine-based inhibitory motif plays in mediating the human CD94/NKG2A inhibitory signal. (PMID:12165520)
• TCR specificity dictates CD94/NKG2A expression by CTL. (PMID:12387742)
• NK cell CD94/NKG2A inhibitory receptors are internalized and recycle independently of inhibitory signaling processes. (PMID:12444112)
• CD94/NKG2A+ NK cells can recognize stressed cells in a peptide-dependent manner. (PMID:12461076)
• CD94 gene expression is regulated by distal and proximal promoters that transcribe unique initial exons specific to each promoter, resulting in two species of transcripts–the previously described CD94 mRNA and a novel CD94C mRNA. (PMID:14607929)
• Aberrant expression of natural killer (NK) receptors CD94/NKG2A may have an impact on the magnitude and direction of dendritic cell activation of T cells under pathological conditions, such as chronic hepatitis C virus infection. (PMID:15528343)
• Expression of the inhibitory NKR (CD94/NKG2A) of the G-CSF mobilized peripheral blood mononuclear cells. (PMID:15561299)
• CD94/NKG2C may constitute an alternative T cell activation pathway capable of driving the expansion and triggering the effector functions of a cytotoxic T cell subset. (PMID:15940674)
• A CD94 alternatively spliced transcript paired with an NKG2B isoform may contribute to the plasticity of the natural killer cell immunological synapse by insuring an adequate inhibitory signal. (PMID:16237464)
• Cytolytic activity levels of purified CD94-expressing cells from 7-day cultures with FK506 were much higher than those from 7-day cultures without FK506. (PMID:16378079)
• Increased expression of CD94/NKG2A in peritoneal NK cells may mediate the resistance of endometriotic tissue to NK cell-mediated lysis, thus contributing to the progression of the disease. (PMID:17706207)
• results 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)
• The results indicated that the high expression of NKG2A/CD94 and low expression of granzyme B may be related with the reduced activity of cord blood NK cells. (PMID:17976318)
• the invariant CD94 chain plays a more dominant role in interacting with HLA-E in comparison to the variable NKG2 chain. (PMID:18083576)
• identified molecular characteristics of an aggressive subset of pediatric patients with AML through a prospective evaluation of CD56+ neural cell adhesion molecule (NCAM) and CD94 expression (PMID:18323797)
• crystal structure of CD94-NKG2A in complex with HLA-E bound to a peptide derived from the leader sequence of HLA-G (PMID:18332182)
• Uncommon endocytic and trafficking pathway of the natural killer cell CD94/NKG2A inhibitory receptor is described. (PMID:18363778)
• 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)
• Under the influence of interleukin-12 stimulation, CD94/NKG2A is transiently inducible in natural killer (NK) cells bearing the homologous CD94/NKG2C-activating receptor, providing a potential negative regulatory feedback mechanism. (PMID:19124726)
• In this work, the glycan ligands of NKG2D and CD94 for the first time were resolved. (PMID:19303396)
• NKG2D and CD94 bind to heparin and sulfate-containing polysaccharides. (PMID:19555665)
• demonstrate that human cytomegalovirus induces an immediate proportional enlargement of a functionally active CD94/NKG2A expressing subset of natural killer cells. (PMID:19782712)
• increased expression on natural killer cells in women with recurrent spontaneous abortion after IVIG therapy (PMID:19811464)
• human CD56(bright) NK cells progress through a continuum of differentiation that ends with a CD94(low)CD56(dim) phenotype. (PMID:19897577)
• CD94/NKG2C might be involved in triggering cytotoxic lymphocytes in patients with Toxic epidermal necrolysis and Stevens-Johnson syndrome (PMID:20132973)
• The differences of CD94 and NKG2 expression between nasal NK/T-cell lymphomas and B cell lymphoma or T cell lymphoma were statistically significant. (PMID:20654155)
• These results suggested that these glycans can interact with NKG2D and CD94 to modulate NK cell-dependent cytotoxicity. (PMID:21212510)
• Loss of CD94 is associated with rheumatoid arthritis. (PMID:22102879)
• Cytotoxicity of CD56(bright) NK cells towards autologous activated CD4+ T cells is mediated through NKG2D, LFA-1 and TRAIL and dampened via CD94/NKG2A (PMID:22384114)
• Results suggested that the low expression level of CD94/NKG2A upon gammadelta T cell activation might lead to the over-activation of gammadelta T cells in patients with SLE. (PMID:22486170)
• Studies indicate that HLA-E interacts with CD94/NKG2 receptors expressed mainly on the surface of natural killer (NK) cells, thus confining its role to the regulation of NK-cell function. (PMID:22576308)
• NKG2C zygosity influences CD94/NKG2C receptor function and the NK-cell compartment redistribution in response to human cytomegalovirus. (PMID:24030638)
• Synergistic inhibition of natural killer cells by the nonsignaling molecule CD94. (PMID:24082146)
• Data indicate that the expression of KLRD1 (CD94) and NKG2E (KLRC3) was reduced in NK-enriched cells in fulminant type 1 diabetes. (PMID:24177169)
• Balance between activating NKG2D, DNAM-1, NKp44 and NKp46 and inhibitory CD94/NKG2A receptors determine natural killer degranulation towards rheumatoid arthritis synovial fibroblasts. (PMID:24673109)
• Data indicate that NKG2 receptor NKG2E was capable of associating with CD94 and DAP12 but that the complex was retained intracellularly at the endoplasmic reticulum. (PMID:24935923)
• it is not clear if high expression of CD94 on peripheral blood NK cells is related to abnormal activity of endometrial NK cells. (PMID:24975965)
• CD94 and NKG2A polymorphisms may contribute to genetic susceptibility to rheumatoid arthritis or affect the response to anti-TNF therapy in patients of Caucasian origin. (PMID:26453102)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-193e13.5	ENSDARG00000052656
danio_rerio		ENSDARG00000074732
danio_rerio	si:dkey-26c10.5	ENSDARG00000088023
danio_rerio	si:ch211-170d8.8	ENSDARG00000090945
mus_musculus	Klrd1	ENSMUSG00000030165
rattus_norvegicus	Klrd1	ENSRNOG00000060246
drosophila_melanogaster	rgn	FBGN0261258
caenorhabditis_elegans		WBGENE00009156
caenorhabditis_elegans		WBGENE00013008

Paralogs (23): CLEC2D (ENSG00000069493), CD69 (ENSG00000110848), CLEC2B (ENSG00000110852), KLRB1 (ENSG00000111796), KLRC1 (ENSG00000134545), KLRG1 (ENSG00000139187), KLRF1 (ENSG00000150045), CLEC1A (ENSG00000150048), CLEC1B (ENSG00000165682), CLEC7A (ENSG00000172243), CLEC12A (ENSG00000172322), OLR1 (ENSG00000173391), KLRC4 (ENSG00000183542), CLEC2A (ENSG00000188393), KLRG2 (ENSG00000188883), CLEC9A (ENSG00000197992), KLRC2 (ENSG00000205809), KLRC3 (ENSG00000205810), KLRK1 (ENSG00000213809), CLEC2L (ENSG00000236279), CLEC12B (ENSG00000256660), KLRF2 (ENSG00000256797), CLEC5A (ENSG00000258227)

Protein

Protein identifiers

Natural killer cells antigen CD94 — Q13241 (reviewed: Q13241)

Alternative names: KP43, Killer cell lectin-like receptor subfamily D member 1, NK cell receptor

All UniProt accessions (6): E9PCX9, Q13241, F5GX94, F5H2B7, F6WZH4, H0YFB8

UniProt curated annotations — full annotation on UniProt →

Function. Immune receptor involved in self-nonself discrimination. In complex with KLRC1 or KLRC2 on cytotoxic and regulatory lymphocyte subsets, recognizes non-classical major histocompatibility (MHC) class Ib molecule HLA-E loaded with self-peptides derived from the signal sequence of classical MHC class Ia and non-classical MHC class Ib molecules. Enables cytotoxic cells to monitor the expression of MHC class I molecules in healthy cells and to tolerate self. Primarily functions as a ligand binding subunit as it lacks the capacity to signal. KLRD1-KLRC1 acts as an immune inhibitory receptor. Key inhibitory receptor on natural killer (NK) cells that regulates their activation and effector functions. Dominantly counteracts T cell receptor signaling on a subset of memory/effector CD8-positive T cells as part of an antigen-driven response to avoid autoimmunity. On intraepithelial CD8-positive gamma-delta regulatory T cells triggers TGFB1 secretion, which in turn limits the cytotoxic programming of intraepithelial CD8-positive alpha-beta T cells, distinguishing harmless from pathogenic antigens. In HLA-E-rich tumor microenvironment, acts as an immune inhibitory checkpoint and may contribute to progressive loss of effector functions of NK cells and tumor-specific T cells, a state known as cell exhaustion. Upon HLA-E-peptide binding, transmits intracellular signals through KLRC1 immunoreceptor tyrosine-based inhibition motifs (ITIMs) by recruiting INPP5D/SHIP-1 and INPPL1/SHIP-2 tyrosine phosphatases to ITIMs, and ultimately opposing signals transmitted by activating receptors through dephosphorylation of proximal signaling molecules. KLRD1-KLRC2 acts as an immune activating receptor. On cytotoxic lymphocyte subsets recognizes HLA-E loaded with signal sequence-derived peptides from non-classical MHC class Ib HLA-G molecules, likely playing a role in the generation and effector functions of adaptive NK cells and in maternal-fetal tolerance during pregnancy. Regulates the effector functions of terminally differentiated cytotoxic lymphocyte subsets, and in particular may play a role in adaptive NK cell response to viral infection. Upon HLA-E-peptide binding, transmits intracellular signals via the adapter protein TYROBP/DAP12, triggering the phosphorylation of proximal signaling molecules and cell activation. (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. Recognizes HLA-E in complex with human cytomegalovirus UL40-derived peptide (VMAPRTLIL) and inhibits NK cell cytotoxicity. (Microbial infection) May recognize HLA-E in complex with 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. On NK cells, may recognize HLA-E in complex with SARS-CoV-2 S/Spike protein S1-derived peptide (LQPRTFLL) expressed on the surface of lung epithelial cells, inducing NK cell exhaustion and dampening antiviral immune surveillance.

Subunit / interactions. Can form disulfide-bonded heterodimer with NKG2 family members KLRC1 and KLRC2. KLRD1-KLRC1 heterodimer interacts with peptide-bound HLA-E-B2M heterotrimeric complex. KLRD1 plays a prominent role in directly interacting with HLA-E. KLRD1-KLRC1 interacts with much higher affinity with peptide-bound HLA-E-B2M than KLRD1-KLRC2. Interacts with the adapter protein TYROBP/DAP12; this interaction is required for cell surface expression and cell activation.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in NK cell subsets (at protein level). Expressed in memory/effector CD8-positive alpha-beta T cell subsets (at protein level). Expressed in melanoma-specific cytotoxic T cell clones (at protein level). Expressed in terminally differentiated cytotoxic gamma-delta T cells (at protein level). KLRD1-KLRC1 and KLRD1-KLRC2 are differentially expressed in NK and T cell populations, with only minor subsets expressing both receptor complexes (at protein level).

Isoforms (3)

UniProt ID	Names	Canonical?
Q13241-1	1, CD94-A	yes
Q13241-2	2, CD94-B
Q13241-3	3, CD94 alt

RefSeq proteins (8): NP_001107868, NP_001337989, NP_001337991, NP_001337992, NP_001401153, NP_001401154, NP_002253, NP_031360 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001304	C-type_lectin-like	Domain
IPR016186	C-type_lectin-like/link_sf	Homologous_superfamily
IPR016187	CTDL_fold	Homologous_superfamily
IPR033992	NKR-like_CTLD	Domain
IPR050919	NKG2/CD94_NK_receptors	Family

Pfam: PF00059

UniProt features (40 total): mutagenesis site 11, strand 7, disulfide bond 5, turn 4, helix 3, topological domain 2, splice variant 2, glycosylation site 2, chain 1, sequence variant 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3BDW	X-RAY DIFFRACTION	2.5
1B6E	X-RAY DIFFRACTION	2.6
3CDG	X-RAY DIFFRACTION	3.4
3CII	X-RAY DIFFRACTION	4.41

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13241-F1	87.89	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.

Disulfide bonds (5): 89–174, 152–166, 58–70, 59, 61–72

Glycosylation sites (2): 83, 132

Mutagenesis-validated functional residues (11):

Position	Phenotype
79	has no impact on the affinity for hla-e.
112	abolishes binding to hla-e.
114	abolishes binding to hla-e.
146	has no impact on the affinity for hla-e.
148	has no impact on the affinity for hla-e.
158	has no impact on the affinity for hla-e.
160	abolishes binding to hla-e.
162	abolishes binding to hla-e.
163	impairs binding to hla-e.
164	impairs binding to hla-e.
168	reduces binding to hla-e.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	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-1280218	Adaptive Immune System
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 337 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOCC_CELL_SURFACE, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_NEGATIVE_REGULATION_OF_NATURAL_KILLER_CELL_MEDIATED_IMMUNITY, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM

GO Biological Process (10): negative regulation of T cell mediated cytotoxicity (GO:0001915), stimulatory C-type lectin receptor signaling pathway (GO:0002223), natural killer cell mediated immunity (GO:0002228), adaptive immune response (GO:0002250), cell surface receptor signaling pathway (GO:0007166), regulation of natural killer cell activation (GO:0032814), negative regulation of natural killer cell mediated cytotoxicity (GO:0045953), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954), immune system process (GO:0002376), innate immune response (GO:0045087)

GO Molecular Function (8): transmembrane signaling receptor activity (GO:0004888), MHC class I protein complex binding (GO:0023024), MHC class Ib protein binding, via antigen binding groove (GO:0023030), HLA-A specific activating MHC class I receptor activity (GO:0030108), carbohydrate binding (GO:0030246), HLA-E specific inhibitory MHC class Ib receptor activity (GO:0062082), protein antigen binding (GO:1990405), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), signaling receptor complex (GO:0043235), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Immune System	2
Adaptive Immune System	1
Innate Immune System	1
DAP12 interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of leukocyte mediated cytotoxicity	2
immune response	2
natural killer cell mediated cytotoxicity	2
regulation of natural killer cell mediated cytotoxicity	2
binding	2
T cell mediated cytotoxicity	1
regulation of T cell mediated cytotoxicity	1
negative regulation of T cell mediated immunity	1
innate immune response activating cell surface receptor signaling pathway	1
cellular response to lectin	1
lymphocyte mediated immunity	1
innate immune response	1
signal transduction	1
natural killer cell activation	1
regulation of lymphocyte activation	1
negative regulation of natural killer cell mediated immunity	1
positive regulation of leukocyte mediated cytotoxicity	1
positive regulation of natural killer cell mediated immunity	1
biological_process	1
defense response to symbiont	1
signaling receptor activity	1
MHC protein complex binding	1
MHC class Ib protein complex binding	1
MHC class Ib protein binding	1
activating MHC class I receptor activity	1
inhibitory MHC class Ib receptor activity	1
antigen binding	1
protein binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
protein-containing complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1760 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLRD1	HLA-E	P13747	999
KLRD1	HLA-C	P04222	994
KLRD1	HLA-G	P17693	994
KLRD1	TYROBP	O43914	991
KLRD1	KLRC1	P26715	986
KLRD1	KLRC2	P26717	986
KLRD1	KLRC3	Q07444	983
KLRD1	KIR2DL1	P43626	936
KLRD1	HSPA4	P34932	935
KLRD1	KIR2DL3	P43628	935
KLRD1	RPL5	P46777	899
KLRD1	CD226	Q15762	881
KLRD1	MICB	P79525	875
KLRD1	NCR1	O76036	870
KLRD1	HLA-A	P01891	866

IntAct

12 interactions, top by confidence:

A	B	Type	Score
KLRD1	KLRC1	psi-mi:“MI:0407”(direct interaction)	0.680
KLRC1	KLRD1	psi-mi:“MI:0407”(direct interaction)	0.680
KLRC2	KLRD1	psi-mi:“MI:0407”(direct interaction)	0.610
B2M	HLA-E	psi-mi:“MI:0915”(physical association)	0.590
KLRD1	HLA-E	psi-mi:“MI:0915”(physical association)	0.400
KLRD1	PRORP	psi-mi:“MI:0914”(association)	0.350
KLRD1	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (105): KLRC1 (Affinity Capture-Western), KLRC2 (Affinity Capture-Western), KLRC3 (Affinity Capture-Western), HLA-E (Reconstituted Complex), KLRC1 (Affinity Capture-Western), TMEM39B (Affinity Capture-MS), CNTNAP3 (Affinity Capture-MS), FAM213A (Affinity Capture-MS), SFXN3 (Affinity Capture-MS), ACAD10 (Affinity Capture-MS), ATP8B2 (Affinity Capture-MS), TMEM183A (Affinity Capture-MS), TUBA3C (Affinity Capture-MS), ADAMTS2 (Affinity Capture-MS), TMED1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0E4BZH1, A4KWA1, D3W0D1, O35778, O54707, P27471, P27812, P27814, P78380, P79391, Q0VCS6, Q0ZUP0, Q0ZUP1, Q12918, Q13241, Q2HXU8, Q38HS3, Q49BZ4, Q58DF9, Q5NKN2, Q5NKN4, Q5QGZ9, Q60651, Q60652, Q60653, Q60660, Q60682, Q63378, Q64329, Q6QLQ4, Q6UVW9, Q80ZC8, Q863H3, Q8BWY2, Q8C567, Q8CJC7, Q8HZR8, Q8MHY9, Q8NC01, Q8VD98

Diamond homologs: C0HKZ6, D3W0D1, D3ZWT9, O70156, P02706, P07307, P08290, P0C7M8, P0C7M9, P10716, P20693, P23806, P27471, P27811, P27812, P27814, P34927, P49300, P49301, P70194, P78380, P79391, Q0H8B9, Q0ZCA7, Q0ZUP0, Q0ZUP1, Q13241, Q149M0, Q28768, Q3LUH2, Q49BZ4, Q5NKN2, Q5NKN4, Q60654, Q67EQ1, Q6QLQ4, Q6UXB4, Q6ZS10, Q7LZ71, Q80ZC8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1080 predictions. Top by Δscore:

Variant	Effect	Δscore
12:10311623:C:G	donor_gain	1.0000
12:10313514:G:GG	donor_gain	1.0000
12:10314774:G:GG	donor_gain	1.0000
12:10308082:CAGG:C	donor_loss	0.9900
12:10308083:AGG:A	donor_loss	0.9900
12:10308084:GGT:G	donor_loss	0.9900
12:10308085:G:T	donor_loss	0.9900
12:10308086:T:G	donor_loss	0.9900
12:10309386:A:AG	acceptor_gain	0.9900
12:10309387:G:GG	acceptor_gain	0.9900
12:10309387:GT:G	acceptor_gain	0.9900
12:10309478:ATT:A	donor_gain	0.9900
12:10309481:G:GG	donor_gain	0.9900
12:10309620:TTATA:T	acceptor_loss	0.9900
12:10309622:ATAGC:A	acceptor_loss	0.9900
12:10309623:TAGC:T	acceptor_loss	0.9900
12:10309624:A:AG	acceptor_gain	0.9900
12:10309624:AGCT:A	acceptor_loss	0.9900
12:10309625:G:GG	acceptor_gain	0.9900
12:10309685:AAAG:A	donor_loss	0.9900
12:10309686:AAG:A	donor_loss	0.9900
12:10309687:AGG:A	donor_loss	0.9900
12:10309688:GGTAG:G	donor_loss	0.9900
12:10309689:GT:G	donor_loss	0.9900
12:10309690:TAGGT:T	donor_loss	0.9900
12:10311608:A:G	donor_gain	0.9900
12:10311622:GC:G	donor_gain	0.9900
12:10314756:A:G	donor_gain	0.9900
12:10314816:TGGA:T	donor_gain	0.9900
12:10314817:GGAG:G	donor_gain	0.9900

AlphaMissense

1190 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:10311546:G:C	W82C	0.984
12:10311546:G:T	W82C	0.984
12:10311495:G:C	W65C	0.982
12:10311495:G:T	W65C	0.982
12:10313484:G:C	W130C	0.979
12:10313484:G:T	W130C	0.979
12:10311553:A:C	S85R	0.976
12:10311555:T:A	S85R	0.976
12:10311555:T:G	S85R	0.976
12:10313442:G:C	W116C	0.974
12:10313442:G:T	W116C	0.974
12:10311565:T:A	C89S	0.973
12:10311566:G:C	C89S	0.973
12:10314773:T:A	C174S	0.961
12:10314774:G:C	C174S	0.961
12:10313478:G:C	W128C	0.957
12:10313478:G:T	W128C	0.957
12:10314707:T:A	C152S	0.955
12:10314708:G:C	C152S	0.955
12:10311567:T:G	C89W	0.952
12:10311566:G:A	C89Y	0.949
12:10311493:T:A	W65R	0.941
12:10311493:T:C	W65R	0.941
12:10314709:C:G	C152W	0.938
12:10311517:T:G	Y73D	0.936
12:10313482:T:A	W130R	0.932
12:10313482:T:C	W130R	0.932
12:10311565:T:C	C89R	0.931
12:10311544:T:A	W82R	0.929
12:10311544:T:C	W82R	0.929

dbSNP variants (sampled 300 via entrez): RS1000014066 (12:10268379 A>G), RS1000026693 (12:10318616 C>T), RS1000075673 (12:10274144 G>A), RS1000103260 (12:10275333 A>G), RS1000144049 (12:10324648 A>G), RS1000157462 (12:10294886 G>A), RS1000199789 (12:10238296 G>A), RS1000200610 (12:10280462 G>A,T), RS1000225611 (12:10297139 G>A), RS1000270753 (12:10250631 T>A), RS1000346656 (12:10238824 A>AT), RS1000352103 (12:10287060 C>G,T), RS1000357448 (12:10244204 C>G,T), RS1000445476 (12:10244754 G>A,C), RS1000452471 (12:10288254 A>C,G)

Disease associations

OMIM: gene MIM:602894 | 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
GCST008022_1	Umami taste perception in obesity with metabolic syndrome	3.000000e-06

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
rs2302489	Efficacy	3	adalimumab;certolizumab pegol;etanercept;glucocorticoids;infliximab;methotrexate	Rheumatoid arthritis

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2302489	KLRD1	3	2.75	1	adalimumab;certolizumab pegol;etanercept;glucocorticoids;infliximab;methotrexate

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	3
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	increases methylation	1
sodium arsenite	decreases expression	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
Acetaminophen	affects cotreatment, decreases expression	1
Dietary Carbohydrates	affects cotreatment, decreases expression	1
Folic Acid	increases expression	1
Mercuric Chloride	increases expression	1
Methotrexate	decreases expression	1
Nickel	increases expression	1
Oxygen	increases expression	1
Silicon Dioxide	decreases expression	1
Zinc	decreases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E6RE	Genomeditech CHO-K1 H_NKG2A+CD94	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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