KLRC3

Summary

KLRC3 (killer cell lectin like receptor C3, HGNC:6376) is a protein-coding gene on chromosome 12p13.2, encoding NKG2-E type II integral membrane protein (Q07444). Plays a role as a receptor for the recognition of MHC class I HLA-E molecules by NK cells and some cytotoxic T-cells.

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. NK cells preferentially express several calcium-dependent (C-type) lectins, which have been implicated in the regulation of NK cell function. KLRC3 is a member of the NKG2 group which are expressed primarily in natural killer (NK) cells and encodes a family of transmembrane proteins characterized by a type II membrane orientation (extracellular C terminus) and the presence of a C-type lectin domain. The NKG2 gene family is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed on NK cells. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 3823 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 45 total
• MANE Select transcript: NM_002261

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6376
Approved symbol	KLRC3
Name	killer cell lectin like receptor C3
Location	12p13.2
Locus type	gene with protein product
Status	Approved
Aliases	NKG2-E
Ensembl gene	ENSG00000205810
Ensembl biotype	protein_coding
OMIM	602892
Entrez	3823

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000381903, ENST00000396439

RefSeq mRNA: 2 — MANE Select: NM_002261 NM_002261, NM_007333

CCDS: CCDS31744, CCDS41755

Canonical transcript exons

ENST00000396439 — 7 exons

Exon	Start	End
ENSE00001490216	10420364	10420595
ENSE00001765674	10419044	10419088
ENSE00001796647	10419866	10419964
ENSE00003467458	10416667	10416767
ENSE00003499621	10418344	10418498
ENSE00003501226	10412315	10412616
ENSE00003662816	10415704	10415794

Expression profiles

Bgee: expression breadth ubiquitous, 114 present calls, max score 85.10.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	85.10	gold quality
granulocyte	CL:0000094	81.18	gold quality
amygdala	UBERON:0001876	71.16	gold quality
temporal lobe	UBERON:0001871	70.50	gold quality
Ammon’s horn	UBERON:0001954	68.64	gold quality
substantia nigra	UBERON:0002038	68.10	gold quality
hypothalamus	UBERON:0001898	67.55	gold quality
blood	UBERON:0000178	66.40	gold quality
anterior cingulate cortex	UBERON:0009835	66.03	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	65.58	gold quality
putamen	UBERON:0001874	65.00	gold quality
caudate nucleus	UBERON:0001873	63.77	gold quality
spleen	UBERON:0002106	63.70	gold quality
prefrontal cortex	UBERON:0000451	63.17	gold quality
cerebral cortex	UBERON:0000956	62.46	gold quality
nucleus accumbens	UBERON:0001882	62.23	gold quality
primary visual cortex	UBERON:0002436	61.87	gold quality
frontal cortex	UBERON:0001870	61.74	gold quality
endometrium	UBERON:0001295	60.54	gold quality
right frontal lobe	UBERON:0002810	60.21	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	59.77	gold quality
lymph node	UBERON:0000029	59.69	gold quality
tonsil	UBERON:0002372	58.49	gold quality
superior frontal gyrus	UBERON:0002661	58.34	gold quality
brain	UBERON:0000955	57.77	gold quality
mucosa of transverse colon	UBERON:0004991	57.33	gold quality
Brodmann (1909) area 9	UBERON:0013540	55.73	gold quality
duodenum	UBERON:0002114	54.63	gold quality
colonic epithelium	UBERON:0000397	54.04	gold quality
right uterine tube	UBERON:0001302	53.57	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-GEOD-70580	yes	155.98
E-MTAB-9467	yes	31.45
E-CURD-122	yes	24.43
E-CURD-88	yes	22.31
E-HCAD-1	yes	19.82
E-CURD-46	yes	14.65
E-MTAB-8410	yes	11.41
E-ANND-3	yes	8.66

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, NCOA1, NCOA2

miRNA regulators (miRDB)

36 targeting KLRC3, 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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4527	99.66	67.43	714
HSA-MIR-6503-5P	99.62	66.96	597
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-6873-5P	98.45	66.14	1417
HSA-MIR-4436B-3P	98.25	65.26	1494

Literature-anchored findings (GeneRIF, showing 6)

• Data indicate that the expression of KLRD1 (CD94) and NKG2E (KLRC3) was reduced in NK-enriched cells in fulminant type 1 diabetes. (PMID:24177169)
• 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)
• KLRC3 gene expression is linked to glioblastoma aggressiveness. (PMID:27641066)
• ADSL is involved in endometrial cancer aggressiveness by regulating expression of killer cell lectin-like receptor C3. (PMID:29467457)
• These observations raise the intriguing possibility that NKG2H may be a novel marker for T cells able to negatively regulate T cell responses. (PMID:29545803)
• DNA Methylation of KLRC1 and KLRC3 in Autoimmune Thyroiditis: Perspective of Different Water Iodine Exposure. (PMID:39401997)

Cross-species orthologs

17 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	Klri2	ENSMUSG00000043932
mus_musculus	Clec2m	ENSMUSG00000047720
mus_musculus	Klre1	ENSMUSG00000050241
mus_musculus	Klri1	ENSMUSG00000067610
mus_musculus	Klrh1	ENSMUSG00000071158
rattus_norvegicus	Klri1	ENSRNOG00000052803
rattus_norvegicus	Clec2m	ENSRNOG00000057254
rattus_norvegicus	Klri2	ENSRNOG00000057643
rattus_norvegicus	Klre1	ENSRNOG00000058714
rattus_norvegicus	Klrh1	ENSRNOG00000059182
drosophila_melanogaster	rgn	FBGN0261258
caenorhabditis_elegans		WBGENE00009156
caenorhabditis_elegans		WBGENE00013008

Paralogs (23): CLEC2D (ENSG00000069493), CD69 (ENSG00000110848), CLEC2B (ENSG00000110852), KLRB1 (ENSG00000111796), KLRD1 (ENSG00000134539), 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), KLRK1 (ENSG00000213809), CLEC2L (ENSG00000236279), CLEC12B (ENSG00000256660), KLRF2 (ENSG00000256797), CLEC5A (ENSG00000258227)

Protein

Protein identifiers

NKG2-E type II integral membrane protein — Q07444 (reviewed: Q07444)

Alternative names: NK cell receptor E, NKG2-E-activating NK receptor

All UniProt accessions (1): Q07444

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role as a receptor for the recognition of MHC class I HLA-E molecules by NK cells and some cytotoxic T-cells.

Subunit / interactions. Can form disulfide-bonded heterodimer with CD94.

Subcellular location. Membrane.

Tissue specificity. Natural killer cells.

Isoforms (2)

UniProt ID	Names	Canonical?
Q07444-1	NKG2-E	yes
Q07444-2	NKG2-H

RefSeq proteins (2): NP_002252, NP_031359 (=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 (22 total): sequence variant 7, glycosylation site 3, topological domain 2, disulfide bond 2, sequence conflict 2, chain 1, splice variant 1, transmembrane region 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q07444-F1	71.04	0.30

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 (2): 117–128, 207–220

Glycosylation sites (3): 100, 149, 179

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 152 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, MODULE_45, GOCC_CELL_SURFACE, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, STOSSI_RESPONSE_TO_ESTRADIOL, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_2NM_UP, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_NATURAL_KILLER_CELL_ACTIVATION, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_REGULATION_OF_LYMPHOCYTE_MEDIATED_IMMUNITY

GO Biological Process (4): stimulatory C-type lectin receptor signaling pathway (GO:0002223), cellular defense response (GO:0006968), regulation of natural killer cell activation (GO:0032814), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954)

GO Molecular Function (2): transmembrane signaling receptor activity (GO:0004888), carbohydrate binding (GO:0030246)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
innate immune response activating cell surface receptor signaling pathway	1
cellular response to lectin	1
defense response	1
natural killer cell activation	1
regulation of lymphocyte activation	1
positive regulation of leukocyte mediated cytotoxicity	1
positive regulation of natural killer cell mediated immunity	1
natural killer cell mediated cytotoxicity	1
regulation of natural killer cell mediated cytotoxicity	1
signaling receptor activity	1
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

438 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLRC3	HLA-E	P13747	986
KLRC3	KLRD1	Q13241	983
KLRC3	TYROBP	O43914	849
KLRC3	KLRC2	P26717	774
KLRC3	KLRB1	Q12918	694
KLRC3	B2M	P01884	585
KLRC3	KLRF1	Q9NZS2	570
KLRC3	NCR1	O76036	517
KLRC3	KIR2DL1	P43626	508
KLRC3	KLRK1	P26718	485
KLRC3	NCR2	O95944	480
KLRC3	NCR3	O14931	479
KLRC3	KIR2DL4	P78400	478
KLRC3	HCST	Q9UBK5	476
KLRC3	KIR2DL3	P43628	444

IntAct

3 interactions, top by confidence:

A	B	Type	Score
KLRC3	RNF13	psi-mi:“MI:0914”(association)	0.350
clpB3	KLRC3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (27): KLRC3 (Reconstituted Complex), KLRC3 (Affinity Capture-Western), GALNT13 (Affinity Capture-MS), TMEM18 (Affinity Capture-MS), SEL1L (Affinity Capture-MS), ITGB5 (Affinity Capture-MS), RNF13 (Affinity Capture-MS), SIDT2 (Affinity Capture-MS), RNF167 (Affinity Capture-MS), TCTN2 (Affinity Capture-MS), SLC47A1 (Affinity Capture-MS), IFNGR1 (Affinity Capture-MS), TMEM62 (Affinity Capture-MS), BACE1 (Affinity Capture-MS), TMEM181 (Affinity Capture-MS)

ESM2 similar proteins: A0A2K5V015, A1YIY0, A8MUZ8, A8MWA4, B8JI71, O08569, P01133, P0DJ43, P14370, P14585, P17630, P19070, P48357, P82279, P97435, Q07444, Q0D2K5, Q28066, Q28660, Q29RU2, Q4KUS1, Q5G872, Q5R6R1, Q5RCW9, Q5T1H1, Q5UKY4, Q5Z5Q3, Q60736, Q63515, Q63722, Q6DFV8, Q6GMZ9, Q6V0K7, Q6ZN79, Q7TSY4, Q811Q4, Q8N2E2, Q8VHS2, Q90Y54, Q95MI4

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	4
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

1195 predictions. Top by Δscore:

Variant	Effect	Δscore
12:10415702:A:AC	donor_gain	1.0000
12:10415703:C:CC	donor_gain	1.0000
12:10415793:TC:T	acceptor_gain	1.0000
12:10415794:CC:C	acceptor_gain	1.0000
12:10415794:CCT:C	acceptor_loss	1.0000
12:10415795:C:A	acceptor_loss	1.0000
12:10415795:C:CC	acceptor_gain	1.0000
12:10415796:T:G	acceptor_loss	1.0000
12:10416665:A:AC	donor_gain	1.0000
12:10416666:C:CA	donor_gain	1.0000
12:10416666:C:CT	donor_gain	1.0000
12:10416666:CT:C	donor_gain	1.0000
12:10416666:CTCA:C	donor_gain	1.0000
12:10416666:CTCAT:C	donor_gain	1.0000
12:10416765:TTT:T	acceptor_gain	1.0000
12:10416765:TTTC:T	acceptor_loss	1.0000
12:10416766:TT:T	acceptor_gain	1.0000
12:10416766:TTCTA:T	acceptor_loss	1.0000
12:10416767:TC:T	acceptor_loss	1.0000
12:10416768:C:CA	acceptor_loss	1.0000
12:10416768:C:CC	acceptor_gain	1.0000
12:10416769:T:C	acceptor_loss	1.0000
12:10417599:T:TA	donor_gain	1.0000
12:10419040:GTAC:G	donor_loss	1.0000
12:10419041:TA:T	donor_loss	1.0000
12:10419042:A:T	donor_loss	1.0000
12:10419043:C:G	donor_loss	1.0000
12:10419087:GA:G	acceptor_gain	1.0000
12:10419089:C:CC	acceptor_gain	1.0000
12:10419864:A:AC	donor_gain	1.0000

AlphaMissense

1582 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:10418416:C:A	W138C	0.965
12:10418416:C:G	W138C	0.965
12:10416699:C:A	W185C	0.928
12:10416699:C:G	W185C	0.928
12:10418407:A:C	S141R	0.923
12:10418407:A:T	S141R	0.923
12:10418409:T:G	S141R	0.923
12:10418467:C:A	W121C	0.906
12:10418467:C:G	W121C	0.906
12:10416721:C:G	R178P	0.904
12:10416735:C:A	W173C	0.901
12:10416735:C:G	W173C	0.901
12:10416701:A:G	W185R	0.895
12:10416701:A:T	W185R	0.895
12:10418469:A:G	W121R	0.892
12:10418469:A:T	W121R	0.892
12:10416737:A:G	W173R	0.881
12:10416737:A:T	W173R	0.881
12:10416723:A:C	F177L	0.879
12:10416723:A:T	F177L	0.879
12:10416725:A:G	F177L	0.879
12:10418418:A:G	W138R	0.860
12:10418418:A:T	W138R	0.860
12:10416675:G:C	F193L	0.856
12:10416675:G:T	F193L	0.856
12:10416677:A:G	F193L	0.856
12:10419914:A:G	C80R	0.849
12:10416722:G:T	R178S	0.837
12:10415762:C:G	C207S	0.836
12:10415763:A:T	C207S	0.836

dbSNP variants (sampled 300 via entrez): RS1000206562 (12:10415088 A>T), RS1000242906 (12:10412250 A>G), RS1001126688 (12:10413888 C>T), RS1002302434 (12:10419879 T>G), RS1002583359 (12:10414345 C>G), RS1002697720 (12:10413968 T>C), RS1003510784 (12:10416567 A>G,T), RS1003701732 (12:10415528 G>A,C), RS1003947585 (12:10418274 A>G), RS1004198531 (12:10412191 T>C), RS1004740261 (12:10412563 T>C), RS1005442331 (12:10415974 G>A), RS1005473497 (12:10415776 A>G), RS1006456864 (12:10417086 A>C), RS1006488211 (12:10416850 T>C)

Disease associations

OMIM: gene MIM:602892 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST004602_154	Mean corpuscular volume	5.000000e-09
GCST004633_24	Neutrophil percentage of white cells	3.000000e-11
GCST008572_12	Composite immunoglobulin trait (IgA/IgG)	3.000000e-06
GCST90002388_422	Lymphocyte count	2.000000e-09
GCST90002393_410	Monocyte count	1.000000e-43
GCST90002394_363	Monocyte percentage of white cells	9.000000e-42
GCST90002400_75	Plateletcrit	3.000000e-17
GCST90002403_217	Red blood cell count	9.000000e-18
GCST90011899_73	Aspartate aminotransferase levels	5.000000e-18

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004587	lymphocyte count
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes
EFO:0007985	platelet crit
EFO:0004305	erythrocyte count
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases expression, affects cotreatment, decreases expression, affects binding, increases reaction (+2 more)	3
Tamoxifen	affects binding, affects expression, decreases reaction, increases reaction, affects reaction (+3 more)	3
Cisplatin	decreases response to substance, increases expression, affects cotreatment, decreases expression	2
Progesterone	affects cotreatment, decreases expression, increases expression	2
Raloxifene Hydrochloride	decreases expression, decreases reaction, affects binding, increases reaction, affects reaction (+2 more)	2
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
hydroxyhydroquinone	increases expression	1
3,4-dichloroaniline	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
pentanal	decreases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Aldehydes	decreases expression	1
Diuron	decreases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Silicon Dioxide	decreases expression	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
Zinc Sulfate	decreases expression	1
Particulate Matter	decreases expression	1

Clinical trials (associated diseases)

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