KLRC1

Summary

KLRC1 (killer cell lectin like receptor C1, HGNC:6374) is a protein-coding gene on chromosome 12p13, encoding NKG2-A/NKG2-B type II integral membrane protein (P26715). Immune inhibitory receptor involved in self-nonself discrimination.

Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. The protein encoded by this gene belongs to the killer cell lectin-like receptor family, also called NKG2 family, which is a group of transmembrane proteins preferentially expressed in NK cells. This family of proteins is characterized by the type II membrane orientation and the presence of a C-type lectin domain. This protein forms a complex with another family member, KLRD1/CD94, and has been implicated in the recognition of the MHC class I HLA-E molecules in NK cells. The genes of NKG2 family members form a killer cell lectin-like receptor gene cluster on chromosome 12. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed.

Source: NCBI Gene 3821 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 29 total
• Druggable target: yes
• MANE Select transcript: NM_002259

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6374
Approved symbol	KLRC1
Name	killer cell lectin like receptor C1
Location	12p13
Locus type	gene with protein product
Status	Approved
Aliases	NKG2-A, NKG2-B, CD159a
Ensembl gene	ENSG00000134545
Ensembl biotype	protein_coding
OMIM	161555
Entrez	3821

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 retained_intron

ENST00000347831, ENST00000359151, ENST00000408006, ENST00000536188, ENST00000537699, ENST00000543893, ENST00000544822

RefSeq mRNA: 5 — MANE Select: NM_002259 NM_001304448, NM_002259, NM_007328, NM_213657, NM_213658

CCDS: CCDS76531, CCDS8625, CCDS8626

Canonical transcript exons

ENST00000359151 — 7 exons

Exon	Start	End
ENSE00000915516	10449914	10449967
ENSE00000915517	10450484	10450579
ENSE00000993571	10453198	10453377
ENSE00001337677	10450970	10451187
ENSE00001633944	10447532	10447632
ENSE00001657718	10449237	10449388
ENSE00002237202	10446028	10446662

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 92.78.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.2435 / max 749.9857, expressed in 112 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129529	1.0834	93
129531	0.0460	14
129530	0.0457	15
129527	0.0382	13
129528	0.0229	12
129526	0.0074	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	92.78	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.62	gold quality
endometrium	UBERON:0001295	75.62	gold quality
blood	UBERON:0000178	75.06	gold quality
spleen	UBERON:0002106	73.47	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	70.14	gold quality
corpus callosum	UBERON:0002336	69.82	gold quality
right uterine tube	UBERON:0001302	68.21	gold quality
upper lobe of left lung	UBERON:0008952	66.99	gold quality
lung	UBERON:0002048	66.93	gold quality
lymph node	UBERON:0000029	66.70	gold quality
mucosa of transverse colon	UBERON:0004991	66.68	gold quality
placenta	UBERON:0001987	66.50	gold quality
rectum	UBERON:0001052	66.19	gold quality
gall bladder	UBERON:0002110	65.90	gold quality
leukocyte	CL:0000738	65.59	gold quality
lower esophagus mucosa	UBERON:0035834	65.44	gold quality
vermiform appendix	UBERON:0001154	65.07	gold quality
body of stomach	UBERON:0001161	64.92	gold quality
small intestine Peyer’s patch	UBERON:0003454	64.58	gold quality
monocyte	CL:0000576	63.70	gold quality
small intestine	UBERON:0002108	63.52	gold quality
stomach	UBERON:0000945	63.47	gold quality
right lung	UBERON:0002167	63.21	gold quality
left uterine tube	UBERON:0001303	61.62	gold quality
omental fat pad	UBERON:0010414	61.12	gold quality
adrenal tissue	UBERON:0018303	61.12	gold quality
calcaneal tendon	UBERON:0003701	61.05	gold quality
descending thoracic aorta	UBERON:0002345	60.49	gold quality
fundus of stomach	UBERON:0001160	59.94	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 20.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	2609.04
E-MTAB-6701	yes	2152.42
E-HCAD-24	yes	2138.77
E-MTAB-6653	yes	1789.90
E-GEOD-139324	yes	1254.90
E-HCAD-36	yes	1238.01
E-CURD-55	yes	1230.38
E-MTAB-10553	yes	1021.69
E-CURD-84	yes	746.57
E-HCAD-4	yes	99.84
E-CURD-122	yes	42.03
E-HCAD-10	yes	38.44
E-MTAB-10287	yes	33.70
E-CURD-46	yes	29.30
E-HCAD-9	yes	26.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA3

miRNA regulators (miRDB)

23 targeting KLRC1, 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-1277-5P	100.00	73.95	5056
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-573	99.55	67.44	955
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-491-3P	98.88	68.86	1224
HSA-MIR-1265	98.36	66.46	598
HSA-MIR-4782-5P	98.35	69.33	1474
HSA-MIR-5706	98.35	69.33	1463
HSA-MIR-217-3P	95.67	68.42	1000

Literature-anchored findings (GeneRIF, showing 40)

• Role that each NKG2A immunoreceptor tyrosine-based inhibitory motif plays in mediating the human CD94/NKG2A inhibitory signal. (PMID:12165520)
• TCR antigenic specificity dictates NKG2A commitment, which critically regulates subsequent activation of 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)
• Aberrant expression of natural killer (NK) receptors NKG2A/CD94 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)
• reveal strict gene regulatory mechanisms for CD94 and NKG2 gene expression on CD4+ cells (PMID:15550116)
• Expression of the inhibitory NKR (CD94/NKG2A) of the G-CSF mobilized peripheral blood mononuclear cells. (PMID:15561299)
• immaturity of NK cells and inhibitory effect of NKG2A override graft versus leukemia effect (PMID:15687235)
• only a subpopulation of NK cells expressing high levels of the inhibitory receptor NKG2A are able to lyse autologous vaccinia-infected targets, and that this is due to selective down-regulation of HLA-E (PMID:16434388)
• identified co-induction of NKG2A and CD56 on activation of TH2 cells (PMID:16690409)
• Prevents actin-dependent recruitment of raft-associated activation receptors complexes to the activating immunologic synapse. (PMID:16951318)
• Results sugges that KLRC1 can be a probable candidate gene for SLE on 12p12.3-13.2, but which is not associated with the disease activity. (PMID:17545086)
• 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)
• 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)
• We show that signalling through NKG2A suppresses TH2 effector function. This may provide a means to modulate Th1/Th2 balance in diseases where Th2 cytokines predominate. (PMID:17927829)
• 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)
• High levels of NKG2A is associated with tongue cancer (PMID:18056444)
• the invariant CD94 chain plays a more dominant role in interacting with HLA-E in comparison to the variable NKG2 chain. (PMID:18083576)
• HIV-1 infection is associated with higher levels NKG2A in the cytotoxic NK subset in HIV-1-infected patients with more advanced disease. (PMID:18172398)
• 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)
• T cells were highly susceptible to NKG2A-mediated inhibition of cytotoxic activity and NKG2A(+) lymphocytes were preferentially attracted by CCR5 ligands induced by hepatitis C virus E2 antigen. (PMID:18500933)
• No significance was observed between the inhibitory (NKG2A) or activating (NKG2C and NKG2D) receptor genotypes and the presence of RF, ANA, or bony erosions in Rheumatoid arthritis. (PMID:18700876)
• NKG2A expression is inversely correlated with the number of coexpressed killer inhibitory receptors (KIR) and is more frequent on KIR3DL2-single positive natural killer cells. (PMID:18941190)
• MICA-NKG2D interaction constitutes a mechanism by which monocytes and NK cells as an early source of IFN-gamma may communicate directly during an innate immune response to infections in humans. (PMID:18981088)
• Data suggest that RNAi-mediated silencing of NKG2A in effector cells could improve the efficacy of cell-based immunotherapies but also show that indirect effects of NKG2A knockdown exist. (PMID:19002424)
• 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)
• expression by Vdelta2+ T cells is higher in pregnant women (PMID:19395088)
• negatively controls decidual NK cell cytotoxicity (PMID:19615756)
• Although the percentages of both NKG2A- and NKG2C-positive NK cells were normal in preeclamptic women, the levels of NKG2A and NKG2C on NK cells were significantly up-regulated in these women (PMID:19694640)
• demonstrate that human cytomegalovirus induces an immediate proportional enlargement of a functionally active CD94/NKG2A expressing subset of natural killer cells. (PMID:19782712)
• increased CD8+ T-cell subsets as well as the abnormal expression of NKG2A and NKG2D on CD3+ T and CD3-CD56 + NK cells may play a role in the etiology of systemic lupus erythematosus (PMID:20012119)
• alloreactivity of a significant fraction of KIR(-) NK cells leads to killing of acute myelogenous leukemia and acute lymphoblastic leukemia blasts that is mediated by NKG2A and LIR-1. (PMID:20139023)
• NK cell NKG2A expression is dysregulated in chronic hepatitis C. NKG2A-positive NK cells are associated with a beneficial response to pegylated interferon and ribavirin therapy. (PMID:20550548)
• 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)
• CD56(dim) NK cells continue to differentiate. During this process, they lose expression of NKG2A, sequentially acquire inhibitory killer cell inhibitory immunoglobulin-like receptors and CD57. (PMID:20696944)
• a new model in which the NK cell differentiation and functional fate are based on a stepwise decrease of NKG2A and acquisition of KIRs (PMID:20700504)
• NKG2A expression on gammadelta lymphoproliferative Disease of Large Granular Lymphocytes correlates with asymptomatic pathology, even in the presence of NKG2C coexpression. (PMID:20952657)
• These results suggested that these glycans can interact with NKG2D and CD94 to modulate NK cell-dependent cytotoxicity. (PMID:21212510)
• The positive expression rate of NKG2D and NKG2A on NK cells and CD3(+) T cells in ALL patients was no significantly different from that in AML patients. (PMID:21518478)

Cross-species orthologs

23 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	Klrc1	ENSMUSG00000030167
mus_musculus	Klrc3	ENSMUSG00000033027
mus_musculus	Klri2	ENSMUSG00000043932
mus_musculus	Clec2m	ENSMUSG00000047720
mus_musculus	Klre1	ENSMUSG00000050241
mus_musculus	Klrc2	ENSMUSG00000052736
mus_musculus	Klri1	ENSMUSG00000067610
mus_musculus	Klrh1	ENSMUSG00000071158
rattus_norvegicus	Klrc2	ENSRNOG00000052467
rattus_norvegicus	Klri1	ENSRNOG00000052803
rattus_norvegicus	Klrc1	ENSRNOG00000055196
rattus_norvegicus	Clec2m	ENSRNOG00000057254
rattus_norvegicus	Klri2	ENSRNOG00000057643
rattus_norvegicus	Klre1	ENSRNOG00000058714
rattus_norvegicus	Klrh1	ENSRNOG00000059182
rattus_norvegicus	Klrc3	ENSRNOG00000065970
drosophila_melanogaster	rgn	FBGN0261258
caenorhabditis_elegans		WBGENE00009156
caenorhabditis_elegans		WBGENE00013008

Paralogs (23): CLEC2D (ENSG00000069493), CD69 (ENSG00000110848), CLEC2B (ENSG00000110852), KLRB1 (ENSG00000111796), KLRD1 (ENSG00000134539), 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

NKG2-A/NKG2-B type II integral membrane protein — P26715 (reviewed: P26715)

Alternative names: CD159 antigen-like family member A, NK cell receptor A, NKG2-A/B-activating NK receptor

All UniProt accessions (3): P26715, F5GYZ0, H0YGB7

UniProt curated annotations — full annotation on UniProt →

Function. Immune inhibitory receptor involved in self-nonself discrimination. In complex with KLRD1 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 molecules. Enables cytotoxic cells to monitor the expression of MHC class I molecules in healthy cells and to tolerate self. Upon HLA-E-peptide binding, transmits intracellular signals through two immunoreceptor tyrosine-based inhibition motifs (ITIMs) by recruiting INPP5D/SHP-1 and INPPL1/SHP-2 tyrosine phosphatases to ITIMs, and ultimately opposing signals transmitted by activating receptors through dephosphorylation of proximal signaling molecules. 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. (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. Heterodimer with KLRD1; disulfide-linked. KLRD1-KLRC1 heterodimer interacts with peptide-bound HLA-E-B2M heterotrimeric complex. Competes with KLRC2 for its interaction with HLA-E. Interacts (via ITIM) with INPP5D/SHIP-1 and INPPL1/SHIP-2 (via SH2 domain).

Subcellular location. Cell membrane.

Tissue specificity. Predominantly expressed in NK cells (at protein level). Expressed in intraepithelial CD8-positive T cell subsets with higher frequency in gamma-delta T cells than alpha-beta T cells (at protein level). Expressed in memory gamma-delta T cells (at protein level). Restricted to a subset of memory/effector CD8-positive alpha-beta T cells (at protein level). Expressed in intratumoral NK and CD8-positive T cells. Expressed in melanoma-specific cytotoxic T cell clones (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).

Post-translational modifications. Phosphorylated.

Domain organisation. The cytosolic N-terminus contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which are essential for the association with INPP5D/SHIP-1 and INPPL1/SHIP-2 phosphatases and functional inhibition.

Induction. Up-regulated in memory CD8-positive alpha-beta T cell clones upon antigen-specific stimulation.

Isoforms (2)

UniProt ID	Names	Canonical?
P26715-1	NKG2-A	yes
P26715-2	NKG2-B

RefSeq proteins (5): NP_001291377, NP_002250, NP_015567, NP_998822, NP_998823 (=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 (45 total): mutagenesis site 16, strand 7, glycosylation site 4, disulfide bond 4, topological domain 2, helix 2, short sequence motif 2, modified residue 2, chain 1, splice variant 1, sequence variant 1, transmembrane region 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3BDW	X-RAY DIFFRACTION	2.5
3CDG	X-RAY DIFFRACTION	3.4
3CII	X-RAY DIFFRACTION	4.41
2RMX	SOLUTION NMR
2YU7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P26715-F1	75.54	0.50

Functional residue map

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

Post-translational modifications (2): 8, 40

Disulfide bonds (4): 116, 119–130, 147–229, 208–221

Glycosylation sites (4): 102, 103, 151, 180

Mutagenesis-validated functional residues (16):

Position	Phenotype
6	decreases interaction with inpp5d/ship-1; when associated a-38.
8	impairs phosphorylation, interaction with inpp5d/ship-1 and nk cell functional inhibition; when associated f-40.
38	decreases interaction with inpp5d/ship-1; when associated a-6.
40	impairs phosphorylation, interaction with inpp5d/ship-1 and nk cell functional inhibition; when associated f-8.
137	reduces binding to hla-e.
163	has no impact on the affinity for hla-e.
167–170	impairs binding to hla-e.
172	has no impact on the affinity for hla-e.
200	has no impact on the affinity for hla-e.
202	has no impact on the affinity for hla-e.
212	reduces binding to hla-e.
213	has no impact on the affinity for hla-e.
215	reduces binding to hla-e.
217	reduces binding to hla-e.
220	has little impact on affinity for hla-e.
223	has no impact on affinity for hla-e.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell

MSigDB gene sets: 240 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, MODULE_64, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, 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

GO Biological Process (13): negative regulation of T cell mediated cytotoxicity (GO:0001915), stimulatory C-type lectin receptor signaling pathway (GO:0002223), adaptive immune response (GO:0002250), CD8-positive, gamma-delta intraepithelial T cell differentiation (GO:0002305), natural killer cell inhibitory signaling pathway (GO:0002769), cell surface receptor signaling pathway (GO:0007166), regulation of natural killer cell activation (GO:0032814), 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), immune system process (GO:0002376), immune response-regulating cell surface receptor signaling pathway (GO:0002768), regulation of natural killer cell mediated cytotoxicity (GO:0042269)

GO Molecular Function (7): transmembrane signaling receptor activity (GO:0004888), MHC class I protein complex binding (GO:0023024), carbohydrate binding (GO:0030246), inhibitory MHC class Ib receptor activity (GO:0062080), HLA-E specific inhibitory MHC class Ib receptor activity (GO:0062082), protein binding (GO:0005515), MHC class Ib receptor activity (GO:0032394)

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-1 pathways:

Category	Pathways
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
natural killer cell mediated cytotoxicity	3
negative regulation of leukocyte mediated cytotoxicity	2
immune response	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
gamma-delta intraepithelial T cell differentiation	1
immune response-inhibiting cell surface receptor signaling pathway	1
signal transduction	1
natural killer cell activation	1
regulation of lymphocyte activation	1
defense response to symbiont	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
immune response-regulating signaling pathway	1
cell surface receptor signaling pathway	1
regulation of leukocyte mediated cytotoxicity	1
regulation of natural killer cell mediated immunity	1
signaling receptor activity	1
MHC protein complex binding	1
MHC class Ib receptor activity	1
inhibitory MHC class Ib receptor activity	1
transmembrane signaling receptor activity	1
MHC class Ib protein binding	1
immune receptor activity	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

1322 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLRC1	HLA-E	P13747	999
KLRC1	HLA-G	P17693	993
KLRC1	KLRD1	Q13241	986
KLRC1	HLA-C	P04222	969
KLRC1	KIR2DL3	P43628	944
KLRC1	MICB	P79525	940
KLRC1	HLA-A	P01891	940
KLRC1	KIR2DL1	P43626	905
KLRC1	HLA-F	P30511	903
KLRC1	LILRB1	Q8NHL6	901
KLRC1	NCR3	O14931	901
KLRC1	PVR	P15151	896
KLRC1	CD274	Q9NZQ7	888
KLRC1	NCR1	O76036	876
KLRC1	CD226	Q15762	866

IntAct

154 interactions, top by confidence:

A	B	Type	Score
KLRC1	MAL	psi-mi:“MI:0915”(physical association)	0.720
KLRC1	PMP22	psi-mi:“MI:0915”(physical association)	0.720
MAL	KLRC1	psi-mi:“MI:0915”(physical association)	0.720
KLRD1	KLRC1	psi-mi:“MI:0407”(direct interaction)	0.680
KLRC1	KLRD1	psi-mi:“MI:0407”(direct interaction)	0.680
KLRC1	CLEC2D	psi-mi:“MI:0915”(physical association)	0.600
KLRC1	EMP3	psi-mi:“MI:0915”(physical association)	0.600
B2M	HLA-E	psi-mi:“MI:0915”(physical association)	0.590
KLRC1	NKG7	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	CD82	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	TMEM54	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	TMEM182	psi-mi:“MI:0915”(physical association)	0.560
SFTPC	KLRC1	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	MS4A13	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	KLRG1	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	LSMEM2	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	CLEC7A	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	PLP1	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	CTXN3	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	ATP6V0B	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	GJB4	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	GPR61	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	CD151	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (163): MAL (Two-hybrid), PMP22 (Two-hybrid), CXCL14 (Reconstituted Complex), KLRC1 (Two-hybrid), KLRC1 (Two-hybrid), KLRC1 (Two-hybrid), KLRC1 (Two-hybrid), KLRC1 (Two-hybrid), KLRC1 (Two-hybrid), KLRC1 (Two-hybrid), KLRC1 (Two-hybrid), KLRC1 (Two-hybrid), KLRC1 (Two-hybrid), KLRC1 (Two-hybrid), KLRC1 (Two-hybrid)

ESM2 similar proteins: A4KWA1, D3W0D1, D4AD02, O54709, O70215, O88713, P20937, P26715, P27471, P27811, P27812, P27814, Q07108, Q0ZUP0, Q0ZUP1, Q12918, Q149M0, Q2HXU8, Q2NL33, Q5NKN2, Q5NKN4, Q5QGZ9, Q60652, Q60654, Q63378, Q64335, Q67EQ0, Q6QLQ4, Q6UXN8, Q80XD9, Q80ZC8, Q8BRU4, Q8BWY2, Q8C1T8, Q8CJC7, Q8MI05, Q8NC01, Q8VD98, Q8VI21, Q95MI5

Diamond homologs: A4KWA1, A4KWA5, A4KWA6, A4KWA8, O89335, P02706, P08290, P0C7M8, P0C7M9, P14371, P24721, P26715, P26717, P34927, P37217, Q07108, Q07444, Q0H8B9, Q0ZCA7, Q5M9I1, Q60660, Q6EIG7, Q6QLQ4, Q6UVW9, Q6UXN8, Q80XD9, Q8BWY2, Q8C1T8, Q8HY02, Q8HY10, Q8HY11, Q8HY12, Q8IUN9, Q8MIS5, Q8N1N0, Q8VI21, Q8WTT0, Q90WJ8, Q91V08, Q92478

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HLA-G	up-regulates	KLRC1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 52 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
ER-Phagosome pathway	5	25.0×	6e-05
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	6	20.1×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor signaling pathway	6	8.5×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

639 predictions. Top by Δscore:

Variant	Effect	Δscore
12:10447530:A:AC	donor_gain	1.0000
12:10447531:C:CC	donor_gain	1.0000
12:10447628:AATTT:A	acceptor_gain	1.0000
12:10447629:ATTT:A	acceptor_gain	1.0000
12:10447630:TTT:T	acceptor_gain	1.0000
12:10447630:TTTC:T	acceptor_loss	1.0000
12:10447631:TT:T	acceptor_gain	1.0000
12:10447631:TTC:T	acceptor_loss	1.0000
12:10447632:TCTAA:T	acceptor_loss	1.0000
12:10447633:C:CC	acceptor_gain	1.0000
12:10447633:C:CG	acceptor_loss	1.0000
12:10447634:T:C	acceptor_loss	1.0000
12:10449385:CGTG:C	acceptor_gain	1.0000
12:10449387:TG:T	acceptor_gain	1.0000
12:10449389:C:CC	acceptor_gain	1.0000
12:10450482:A:AC	donor_gain	1.0000
12:10450483:C:CC	donor_gain	1.0000
12:10451186:CT:C	acceptor_gain	1.0000
12:10451188:C:CC	acceptor_gain	1.0000
12:10446815:A:C	donor_gain	0.9900
12:10447531:CT:C	donor_gain	0.9900
12:10447531:CTCA:C	donor_gain	0.9900
12:10447531:CTCAT:C	donor_gain	0.9900
12:10449232:CTTAC:C	donor_loss	0.9900
12:10449234:T:TG	donor_loss	0.9900
12:10449235:A:AC	donor_gain	0.9900
12:10449236:C:CC	donor_gain	0.9900
12:10449386:G:C	acceptor_gain	0.9900
12:10449386:GTG:G	acceptor_gain	0.9900
12:10449968:C:CC	acceptor_gain	0.9900

AlphaMissense

1531 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:10449306:C:A	W140C	0.963
12:10449306:C:G	W140C	0.963
12:10449297:A:C	S143R	0.962
12:10449297:A:T	S143R	0.962
12:10449299:T:G	S143R	0.962
12:10447600:C:A	W174C	0.947
12:10447600:C:G	W174C	0.947
12:10449357:C:A	W123C	0.938
12:10449357:C:G	W123C	0.938
12:10449359:A:G	W123R	0.936
12:10449359:A:T	W123R	0.936
12:10447564:C:A	W186C	0.932
12:10447564:C:G	W186C	0.932
12:10447602:A:G	W174R	0.924
12:10447602:A:T	W174R	0.924
12:10446567:C:G	C229S	0.918
12:10446568:A:T	C229S	0.918
12:10446630:C:G	C208S	0.915
12:10446631:A:T	C208S	0.915
12:10447586:C:G	R179P	0.913
12:10449286:C:G	C147S	0.912
12:10449287:A:T	C147S	0.912
12:10447566:A:G	W186R	0.899
12:10447566:A:T	W186R	0.899
12:10449285:A:C	C147W	0.894
12:10446591:C:G	C221S	0.888
12:10446592:A:T	C221S	0.888
12:10446563:C:A	K230N	0.881
12:10446563:C:G	K230N	0.881
12:10449287:A:G	C147R	0.881

dbSNP variants (sampled 300 via entrez): RS1000090298 (12:10451503 A>C,G), RS1000255643 (12:10448997 T>C,G), RS1000475424 (12:10455035 T>C), RS1000508015 (12:10447122 C>G), RS1001175658 (12:10444912 T>C,G), RS1001636100 (12:10450051 G>A,T), RS1001730956 (12:10450421 T>A,C), RS1001927326 (12:10447830 C>A), RS1002036655 (12:10453984 T>C), RS1002213061 (12:10445789 T>A), RS1002559055 (12:10453594 A>G), RS1002979307 (12:10442142 A>G), RS1003216908 (12:10450863 C>A,G,T), RS1003403388 (12:10448891 CTT>C), RS1003665846 (12:10455721 A>G)

Disease associations

OMIM: gene MIM:161555 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST004608_176	Granulocyte percentage of myeloid white cells	1.000000e-18
GCST004609_192	Monocyte percentage of white cells	1.000000e-16
GCST004625_120	Monocyte count	5.000000e-14
GCST90002385_222	High light scatter reticulocyte count	1.000000e-09
GCST90002390_50	Mean corpuscular hemoglobin	4.000000e-19
GCST90002392_372	Mean corpuscular volume	1.000000e-27
GCST90002396_518	Mean reticulocyte volume	3.000000e-18
GCST90002397_418	Mean spheric corpuscular volume	4.000000e-29
GCST90002405_300	Reticulocyte count	7.000000e-10
GCST90013663_24	Alanine aminotransferase levels	2.000000e-11
GCST90013664_84	Aspartate aminotransferase levels	5.000000e-20

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0005091	monocyte count
EFO:0007986	reticulocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630892 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs7301582	Efficacy	3	adalimumab;certolizumab pegol;etanercept;glucocorticoids;infliximab;methotrexate	Rheumatoid arthritis

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7301582	KLRC1	3	2.25	1	adalimumab;certolizumab pegol;etanercept;glucocorticoids;infliximab;methotrexate
rs2734414	KLRC1		0.00	0
rs2734440	KLRC1		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
monalizumab	Binding	10.57	pKd

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, affects methylation	2
Silicon Dioxide	decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
(+)-JQ1 compound	decreases expression	1
Pemetrexed	affects response to substance, affects expression	1
Aldehydes	decreases expression	1
Biological Factors	increases expression	1
Endosulfan	decreases expression	1
Estradiol	increases expression, affects binding, affects reaction, increases reaction	1
Folic Acid	affects expression, affects response to substance	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Tamoxifen	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	affects expression	1
Raloxifene Hydrochloride	increases expression	1

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8JE	Abcam HCT 116 KLRC1 KO	Cancer cell line	Male
CVCL_B9LP	Abcam A-549 KLRC1 KO	Cancer cell line	Male
CVCL_D2G1	Abcam MCF-7 KLRC1 KO	Cancer cell line	Female
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.