KLRC4

Summary

KLRC4 (killer cell lectin like receptor C4, HGNC:6377) is a protein-coding gene on chromosome 12p13.2, encoding NKG2-F type II integral membrane protein (O43908). May play a role as a receptor for the recognition of MHC class I HLA-E molecules by NK 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. This gene is a member of the NKG2 group of genes that are expressed primarily in natural killer (NK) cells. These family members encode transmembrane proteins that are characterized by a type II membrane orientation (have an extracellular C-terminus) and the presence of a C-type lectin domain. This family member is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed in NK cells. Read-through transcription exists between this gene and the downstream KLRK1 (killer cell lectin-like receptor subfamily K, member 1) family member.

Source: NCBI Gene 8302 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 19 total — 1 pathogenic
• Phenotypes (HPO): 85
• MANE Select transcript: NM_013431

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6377
Approved symbol	KLRC4
Name	killer cell lectin like receptor C4
Location	12p13.2
Locus type	gene with protein product
Status	Approved
Aliases	NKG2-F
Ensembl gene	ENSG00000183542
Ensembl biotype	protein_coding
OMIM	602893
Entrez	8302

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000309384, ENST00000718241, ENST00000718242

RefSeq mRNA: 1 — MANE Select: NM_013431 NM_013431

CCDS: CCDS8624

Canonical transcript exons

ENST00000309384 — 4 exons

Exon	Start	End
ENSE00001145174	10409389	10409757
ENSE00003618826	10408912	10409010
ENSE00003686599	10408329	10408382
ENSE00004034489	10407384	10407789

Expression profiles

Bgee: expression breadth ubiquitous, 156 present calls, max score 78.32.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	78.32	gold quality
lymph node	UBERON:0000029	68.97	gold quality
gall bladder	UBERON:0002110	68.71	gold quality
spleen	UBERON:0002106	67.33	gold quality
corpus callosum	UBERON:0002336	65.63	gold quality
vermiform appendix	UBERON:0001154	64.78	gold quality
right lung	UBERON:0002167	64.63	gold quality
rectum	UBERON:0001052	64.17	gold quality
right uterine tube	UBERON:0001302	63.32	gold quality
small intestine Peyer’s patch	UBERON:0003454	61.10	gold quality
caecum	UBERON:0001153	60.97	gold quality
amygdala	UBERON:0001876	60.53	gold quality
blood	UBERON:0000178	60.11	gold quality
upper lobe of left lung	UBERON:0008952	59.58	gold quality
upper lobe of lung	UBERON:0008948	59.13	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	58.94	gold quality
small intestine	UBERON:0002108	58.76	gold quality
right frontal lobe	UBERON:0002810	58.23	gold quality
anterior cingulate cortex	UBERON:0009835	57.67	gold quality
smooth muscle tissue	UBERON:0001135	57.64	gold quality
cingulate cortex	UBERON:0003027	57.64	gold quality
spinal cord	UBERON:0002240	57.16	gold quality
decidua	UBERON:0002450	56.55	gold quality
mucosa of transverse colon	UBERON:0004991	56.33	gold quality
body of stomach	UBERON:0001161	56.09	gold quality
hypothalamus	UBERON:0001898	55.86	gold quality
substantia nigra	UBERON:0002038	55.46	gold quality
omental fat pad	UBERON:0010414	55.12	gold quality
peritoneum	UBERON:0002358	55.08	gold quality
caudate nucleus	UBERON:0001873	55.00	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

18 targeting KLRC4, 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-3924	100.00	72.09	2394
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-548AO-5P	98.55	69.57	1362
HSA-MIR-548AX	98.55	69.58	1362
HSA-MIR-499B-5P	98.35	68.39	988
HSA-MIR-5585-5P	97.95	68.80	1024

Literature-anchored findings (GeneRIF, showing 6)

• NKG2F is expressed in NK cells and can associate with DAP12. (PMID:15140575)
• NKG2F was expressed on surface of human blood NK cells, and may be up-regulated at mRNA level and protein level after IL-2 or IL-15 stimulation. (PMID:20811687)
• CCR1, KLRC4, IL12A-AS1, STAT4, and ERAP1 are bona fide susceptibility genes for Behcet’s disease. (PMID:26097239)
• This study demonstrates that the MBL2/rs1800450 and KLRC4/rs2617170 are susceptibility factors for Behcet’s disease in a Chinese Han population. (PMID:28706259)
• Screening for the Biomarkers Associated with Myocardial Infarction by Bioinformatics Analysis. (PMID:31502863)
• Novel Association of KLRC4-KLRK1 Gene Polymorphisms with Susceptibility and Progression of Antithyroid Drug-Induced Agranulocytosis. (PMID:38237612)

Cross-species orthologs

15 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
rattus_norvegicus	Klri1	ENSRNOG00000052803
rattus_norvegicus	Clec2m	ENSRNOG00000057254
rattus_norvegicus	Klri2	ENSRNOG00000057643
rattus_norvegicus	Klre1	ENSRNOG00000058714
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), CLEC2A (ENSG00000188393), KLRG2 (ENSG00000188883), CLEC9A (ENSG00000197992), KLRC2 (ENSG00000205809), KLRC3 (ENSG00000205810), KLRK1 (ENSG00000213809), CLEC2L (ENSG00000236279), CLEC12B (ENSG00000256660), KLRF2 (ENSG00000256797), CLEC5A (ENSG00000258227)

Protein

Protein identifiers

NKG2-F type II integral membrane protein — O43908 (reviewed: O43908)

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

All UniProt accessions (1): O43908

UniProt curated annotations — full annotation on UniProt →

Function. May play a role as a receptor for the recognition of MHC class I HLA-E molecules by NK cells.

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

Subcellular location. Membrane.

Tissue specificity. Natural killer cells.

RefSeq proteins (1): NP_038459* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016186	C-type_lectin-like/link_sf	Homologous_superfamily
IPR016187	CTDL_fold	Homologous_superfamily
IPR050919	NKG2/CD94_NK_receptors	Family

UniProt features (8 total): topological domain 2, sequence variant 2, chain 1, transmembrane region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43908-F1	60.03	0.03

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 289 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, MORF_MSH3, MORF_BRCA1, GOCC_CELL_SURFACE, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, STOSSI_RESPONSE_TO_ESTRADIOL, MORF_RAD51L3, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, MORF_CTSB, MORF_IL4

GO Biological Process (2): stimulatory C-type lectin receptor signaling pathway (GO:0002223), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954)

GO Molecular Function (1): transmembrane signaling receptor activity (GO:0004888)

GO Cellular Component (2): external side of plasma membrane (GO:0009897), 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
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
plasma membrane	1
cell surface	1
side of membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

448 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLRC4	KLRK1	P26718	920
KLRC4	TYROBP	O43914	832
KLRC4	CLEC1B	Q9P126	801
KLRC4	HLA-E	P13747	782
KLRC4	CLEC2B	Q92478	780
KLRC4	CLEC1A	Q8NC01	634
KLRC4	ERAP1	Q9NZ08	628
KLRC4	KLRB1	Q12918	609
KLRC4	KLRF1	Q9NZS2	552
KLRC4	CCR1	P32246	506
KLRC4	STAT4	Q14765	506
KLRC4	IL23R	Q5VWK5	479
KLRC4	UBAC2	Q8NBM4	470
KLRC4	CD69	Q07108	436
KLRC4	IL12RB2	Q99665	431
KLRC4	FUT2	Q10981	431

IntAct

5 interactions, top by confidence:

A	B	Type	Score
H2BC9	KLRC4	psi-mi:“MI:0915”(physical association)	0.400
KLRC4	SSR3	psi-mi:“MI:0915”(physical association)	0.400
KLRC4	RAP1BL	psi-mi:“MI:0914”(association)	0.350
KLRC4	RAP1A	psi-mi:“MI:0914”(association)	0.350

BioGRID (37): SSR3 (Proximity Label-MS), OTULIN (Affinity Capture-MS), PDXDC1 (Affinity Capture-MS), PRMT9 (Affinity Capture-MS), SLC7A3 (Affinity Capture-MS), GPD1L (Affinity Capture-MS), SPPL2B (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), EDNRB (Affinity Capture-MS), USP30 (Affinity Capture-MS), VMP1 (Affinity Capture-MS), UGT8 (Affinity Capture-MS), TMTC3 (Affinity Capture-MS), SLC12A7 (Affinity Capture-MS), SIDT2 (Affinity Capture-MS)

ESM2 similar proteins: A4KWA8, B2KG20, D3W0D1, D4AD02, O43908, O54709, O70215, O88713, P20937, P26715, P26717, P27811, P27812, P37217, Q07444, Q149M0, Q2HXU8, Q2NL33, Q504P2, Q5DT36, Q5DT37, Q5DT39, Q5M9I1, Q5QGZ9, Q60651, Q60652, Q60653, Q60654, Q60682, Q64329, Q64335, Q67EQ0, Q6UXN8, Q80XD9, Q80ZC8, Q8BRU4, Q8CJC7, Q8MI05, Q8VI21, Q95MI1

Diamond homologs: O43908, P26715, P26717, Q07444, Q13241, Q80ZC8, Q8MHY9, Q95MI1, Q95MI4, Q95MI5, Q9GLF5, Q9GME8, Q9MZ41, Q9MZJ3, Q9MZK6, Q9MZK9, A4KWA6, A4KWA8, O35778, O54709, P14370, P20937, P21063, P22897, P24765, P49259, P49260, P81397, Q0H8B9, Q2HXU8, Q2LK54, Q38HS3, Q504P2, Q5QGZ9, Q60651, Q60654, Q63378, Q71RQ0, Q80XD9, Q86NG3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	17
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1527669	GRCh37/hg19 12p13.33-12.1(chr12:173786-25286865)	Pathogenic

SpliceAI

677 predictions. Top by Δscore:

Variant	Effect	Δscore
12:10407786:CGTG:C	acceptor_gain	1.0000
12:10407788:TGCT:T	acceptor_loss	1.0000
12:10407790:C:CC	acceptor_gain	1.0000
12:10409383:TTTTA:T	donor_loss	1.0000
12:10409384:TTTA:T	donor_loss	1.0000
12:10409385:TTA:T	donor_loss	1.0000
12:10409385:TTAC:T	donor_loss	1.0000
12:10409386:TACC:T	donor_loss	1.0000
12:10409386:TACCT:T	donor_loss	1.0000
12:10409387:A:AT	donor_loss	1.0000
12:10409388:C:CA	donor_loss	1.0000
12:10407629:GTCTT:G	donor_loss	0.9900
12:10407630:TCTTA:T	donor_loss	0.9900
12:10407631:CTTAC:C	donor_loss	0.9900
12:10407632:TTA:T	donor_loss	0.9900
12:10407633:TACCA:T	donor_loss	0.9900
12:10407634:A:AC	donor_gain	0.9900
12:10407634:ACC:A	donor_loss	0.9900
12:10407635:C:CC	donor_gain	0.9900
12:10407635:C:CT	donor_loss	0.9900
12:10407643:T:TA	donor_gain	0.9900
12:10407787:G:C	acceptor_gain	0.9900
12:10407787:GTG:G	acceptor_gain	0.9900
12:10407788:TG:T	acceptor_gain	0.9900
12:10407791:T:G	acceptor_loss	0.9900
12:10408324:TGTA:T	donor_loss	0.9900
12:10408325:GTA:G	donor_loss	0.9900
12:10408326:TAC:T	donor_loss	0.9900
12:10408327:AC:A	donor_loss	0.9900
12:10408328:CCTTT:C	donor_gain	0.9900

AlphaMissense

1026 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:10407758:C:A	W124C	0.791
12:10407758:C:G	W124C	0.791
12:10408960:A:G	C80R	0.790
12:10407760:A:G	W124R	0.785
12:10407760:A:T	W124R	0.785
12:10407707:C:A	W141C	0.737
12:10407707:C:G	W141C	0.737
12:10408953:A:T	V82D	0.647
12:10407739:A:G	C131R	0.646
12:10407659:A:C	F157L	0.640
12:10407659:A:T	F157L	0.640
12:10407661:A:G	F157L	0.640
12:10407738:C:G	C131S	0.632
12:10407739:A:T	C131S	0.632
12:10408969:C:G	G77R	0.628
12:10408969:C:T	G77R	0.628
12:10407737:A:C	C131W	0.617
12:10407736:A:C	Y132D	0.615
12:10407756:A:G	I125T	0.613
12:10408950:A:G	L83P	0.587
12:10407772:A:G	C120R	0.581
12:10407770:A:C	C120W	0.572

dbSNP variants (sampled 300 via entrez): RS1000493383 (12:10407897 A>C,G,T), RS1000814830 (12:10408166 T>C), RS1000944291 (12:10407228 A>G), RS1001799321 (12:10410989 G>C), RS1002676637 (12:10410626 T>C,G), RS1003586464 (12:10409066 T>C,G), RS1003878762 (12:10409325 C>T), RS1005126524 (12:10407720 T>C), RS1005934790 (12:10411426 A>G), RS1006650892 (12:10408099 G>C), RS1006945732 (12:10408424 C>A), RS1007604675 (12:10409825 A>G), RS1010834263 (12:10408568 T>G), RS1011063987 (12:10411696 C>T), RS1011723826 (12:10410525 G>A)

Disease associations

OMIM: gene MIM:602893 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

85 total (30 of 85 shown, HPO-id order):

HPO	Term
HP:0000031	Epididymitis
HP:0000083	Renal insufficiency
HP:0000099	Glomerulonephritis
HP:0000155	Oral ulcer
HP:0000488	Retinopathy
HP:0000518	Cataract
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000708	Atypical behavior
HP:0000737	Irritability
HP:0001061	Acne
HP:0001097	Keratoconjunctivitis sicca
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001269	Hemiparesis
HP:0001287	Meningitis
HP:0001288	Gait disturbance
HP:0001289	Confusion
HP:0001347	Hyperreflexia
HP:0001369	Arthritis
HP:0001482	Subcutaneous nodule
HP:0001637	Abnormal myocardium morphology
HP:0001653	Mitral regurgitation
HP:0001658	Myocardial infarction
HP:0001659	Aortic regurgitation
HP:0001701	Pericarditis
HP:0001733	Pancreatitis
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001945	Fever

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001804_3	Behcet’s disease	1.000000e-09
GCST004346_53	Psoriasis	4.000000e-09

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2734565	KLRC4		0.00	0
rs1154831	KLRC4		0.00	0

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
Arbutin	increases expression	1
Estradiol	affects expression	1
Silicon Dioxide	decreases expression	1
Tamoxifen	affects expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	increases expression	1
Raloxifene Hydrochloride	affects expression	1

Clinical trials (associated diseases)

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