KLRF1

Summary

KLRF1 (killer cell lectin like receptor F1, HGNC:13342) is a protein-coding gene on chromosome 12p13.31, encoding Killer cell lectin-like receptor subfamily F member 1 (Q9NZS2). Functions as an activating receptor involved in immunosurveillance upon binding to various ligands displayed at the surface of myeloid cells.

KLRF1, an activating homodimeric C-type lectin-like receptor (CTLR), is expressed on nearly all natural killer (NK) cells and stimulates their cytoxicity and cytokine release (Kuttruff et al., 2009 [PubMed 18922855]).

Source: NCBI Gene 51348 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 8 total
• MANE Select transcript: NM_016523

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13342
Approved symbol	KLRF1
Name	killer cell lectin like receptor F1
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	CLEC5C, NKp80
Ensembl gene	ENSG00000150045
Ensembl biotype	protein_coding
OMIM	605029
Entrez	51348

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000279545, ENST00000354855, ENST00000537723, ENST00000545196, ENST00000612321, ENST00000616259, ENST00000617793, ENST00000617889

RefSeq mRNA: 4 — MANE Select: NM_016523 NM_001291822, NM_001291823, NM_001366534, NM_016523

CCDS: CCDS41750, CCDS76526, CCDS76527, CCDS91652

Canonical transcript exons

ENST00000617889 — 6 exons

Exon	Start	End
ENSE00000993552	9833303	9833452
ENSE00000993555	9832316	9832414
ENSE00001321345	9827481	9827629
ENSE00003458838	9842321	9842433
ENSE00003732891	9841812	9841951
ENSE00003844899	9844418	9845005

Expression profiles

Bgee: expression breadth ubiquitous, 167 present calls, max score 97.81.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.8002 / max 782.0913, expressed in 87 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124099	0.7630	59
124097	0.4906	57
124100	0.2777	47
124098	0.1995	38
124096	0.0694	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.81	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.78	gold quality
blood	UBERON:0000178	86.18	gold quality
spleen	UBERON:0002106	86.05	gold quality
leukocyte	CL:0000738	79.86	gold quality
mononuclear cell	CL:0000842	78.25	gold quality
monocyte	CL:0000576	77.65	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.47	gold quality
bone marrow	UBERON:0002371	73.02	gold quality
right lobe of liver	UBERON:0001114	71.78	gold quality
right lung	UBERON:0002167	71.39	gold quality
upper lobe of left lung	UBERON:0008952	70.94	gold quality
lymph node	UBERON:0000029	70.47	gold quality
upper lobe of lung	UBERON:0008948	69.41	gold quality
bone marrow cell	CL:0002092	68.92	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	68.51	gold quality
palpebral conjunctiva	UBERON:0001812	67.33	gold quality
gall bladder	UBERON:0002110	65.55	gold quality
nasal cavity mucosa	UBERON:0001826	65.30	gold quality
subcutaneous adipose tissue	UBERON:0002190	63.91	gold quality
adipose tissue of abdominal region	UBERON:0007808	63.83	gold quality
omental fat pad	UBERON:0010414	63.82	gold quality
peritoneum	UBERON:0002358	63.76	gold quality
lung	UBERON:0002048	63.54	gold quality
adipose tissue	UBERON:0001013	63.35	gold quality
lower esophagus mucosa	UBERON:0035834	63.30	gold quality
rectum	UBERON:0001052	63.00	gold quality
connective tissue	UBERON:0002384	62.46	gold quality
vermiform appendix	UBERON:0001154	62.00	gold quality
minor salivary gland	UBERON:0001830	61.78	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	1073.42
E-GEOD-70580	yes	1048.93
E-GEOD-139324	yes	912.20
E-MTAB-6701	yes	904.59
E-HCAD-9	yes	900.12
E-HCAD-32	yes	618.06
E-HCAD-4	yes	179.13
E-HCAD-1	yes	157.65
E-MTAB-9467	yes	65.23
E-CURD-122	yes	56.25
E-CURD-46	yes	32.14
E-HCAD-10	yes	27.72
E-CURD-88	yes	23.57
E-ANND-3	yes	23.43
E-MTAB-6678	yes	13.35

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting KLRF1, 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-6127	100.00	66.76	2188
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4434	99.10	67.01	1984

Literature-anchored findings (GeneRIF, showing 7)

• NKp80 is expressed on a highly responsive subset of effector memory CD8 T cells with an inflammatory NK-like phenotype and promotes T-cell responses toward AICL-expressing cells. (PMID:18922855)
• Activating receptor NKp80 induces cytotoxicity by using an atypical hemi-ITAM amino acid seqeuence and the Syk-kinase pathway. (PMID:21149606)
• IL-15+IL-12 has an immunomodulatory effect on NK cell subsets from HIV-infected individuals viz down-regulation of iNKRs, elevation of activatory receptors NKp46 and NKG2D, and induction of coreceptor NKp80. (PMID:22715368)
• Two non-consensus amino acids of NKp80, in particular arginine 6, critically impair both hemi-immunoreceptor tyrosine-based activation motif phosphorylation and Syk recruitment. (PMID:23609447)
• our data report a previously unrecognized regulatory circuit enabling autonomous control of human NK cell responses via the NKp80-AICL axis. (PMID:23929856)
• In the second trimester, functional markers of Decidual natural killer activation, i.e., angiogenic factor production (e.g., vascular endothelial growth factor, interleukin-8, interferon-gamma), remained stable despite an increase in NKp80 or NKG2D surface expression. (PMID:26277900)
• NKp80 is a marker of natural killer (NK) cell maturity in secondary lymphoid tissues and supports NK cell development through a stage 4a intermediate with ILC3-associated features. (PMID:27373165)

Cross-species orthologs

7 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
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), 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

Killer cell lectin-like receptor subfamily F member 1 — Q9NZS2 (reviewed: Q9NZS2)

Alternative names: Activating coreceptor NKp80, C-type lectin domain family 5 member C

All UniProt accessions (4): Q9NZS2, Q4KMZ4, Q4KN05, Q4KN30

UniProt curated annotations — full annotation on UniProt →

Function. Functions as an activating receptor involved in immunosurveillance upon binding to various ligands displayed at the surface of myeloid cells. Upon interaction with CLEC2B ligand, stimulates NK-cell cytotoxicity and cytokine production leading to the cytolysis of malignant CLEC2B-expressing myeloid cells. Actviation of the common cytotoxicity pathway involves SRC and SYK kinases.

Subunit / interactions. Homodimer. Interacts with CLEC2B.

Subcellular location. Membrane.

Tissue specificity. Strongly expressed in peripheral blood leukocytes and spleen, with weaker expression in lymph node and adult liver, and no expression detected in bone marrow, thymus, and fetal liver. Not expressed in brain, heart, placenta, lung, kidney, skeletal muscle, and pancreas. Within peripheral blood leukocyte and immunocyte cell lines, expression was predominant in NK cells but was also detected in monocytes.

Post-translational modifications. Phosphorylated on Tyr-7; this phosphorylation is required for NKp80/KLRF1-mediated cytotoxicity.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NZS2-1	1	yes
Q9NZS2-2	2, KLRF1-s1
Q9NZS2-3	3, KLRF1-s3
Q9NZS2-4	4, KLRF1-s2

RefSeq proteins (4): NP_001278751, NP_001278752, NP_001353463, NP_057607* (*=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
IPR051379	C-type_Lectin_Receptor_IMM	Family

Pfam: PF00059

UniProt features (19 total): splice variant 5, glycosylation site 4, topological domain 2, disulfide bond 2, chain 1, sequence variant 1, mutagenesis site 1, transmembrane region 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8QMD	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZS2-F1	78.70	0.56

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 (1): 7

Disulfide bonds (2): 142–229, 208–221

Glycosylation sites (4): 77, 91, 96, 176

Mutagenesis-validated functional residues (1):

Position	Phenotype
7	complete loss of cytolysis.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 85 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, JAEGER_METASTASIS_DN, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, KESHELAVA_MULTIPLE_DRUG_RESISTANCE, GNF2_IL2RB, GOBP_ALPHA_BETA_T_CELL_ACTIVATION, GNF2_PTPN4, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, HAHTOLA_SEZARY_SYNDROM_DN, GOBP_LYMPHOCYTE_ACTIVATION, GOBP_NK_T_CELL_ACTIVATION, GNF2_CD7, KUMAR_PATHOGEN_LOAD_BY_MACROPHAGES

GO Biological Process (4): cell surface receptor signaling pathway (GO:0007166), innate immune response (GO:0045087), NK T cell activation (GO:0051132), immune system process (GO:0002376)

GO Molecular Function (4): transmembrane signaling receptor activity (GO:0004888), carbohydrate binding (GO:0030246), MHC class I receptor activity (GO:0032393), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Adaptive Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
signal transduction	1
immune response	1
defense response to symbiont	1
alpha-beta T cell activation	1
biological_process	1
signaling receptor activity	1
transmembrane signaling receptor activity	1
MHC class I protein binding	1
immune receptor activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1070 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLRF1	CLEC2B	Q92478	987
KLRF1	SLAMF6	Q96DU3	928
KLRF1	CLEC1B	Q9P126	834
KLRF1	NCR1	O76036	804
KLRF1	NCR2	O95944	793
KLRF1	CD226	Q15762	791
KLRF1	CLEC2A	Q6UVW9	775
KLRF1	NCR3	O14931	728
KLRF1	NCR3LG1	Q68D85	684
KLRF1	MICB	P79525	675
KLRF1	KIR3DL1	P43629	672
KLRF1	CD48	P09326	647
KLRF1	CD160	O95971	631
KLRF1	SLAMF7	Q9NQ25	623
KLRF1	FCGR3A	P08637	598

IntAct

3 interactions, top by confidence:

A	B	Type	Score
CLEC2B	KLRF1	psi-mi:“MI:0407”(direct interaction)	0.440
KLRF1	GAPDHS	psi-mi:“MI:0914”(association)	0.350

BioGRID (17): GAPDHS (Affinity Capture-MS), TOMM40 (Affinity Capture-MS), REEP5 (Affinity Capture-MS), CBWD1 (Affinity Capture-MS), REEP6 (Affinity Capture-MS), KLRF1 (Synthetic Growth Defect), REEP6 (Affinity Capture-MS), GAPDHS (Affinity Capture-MS), TOMM40 (Affinity Capture-MS), REEP5 (Affinity Capture-MS), CBWD1 (Affinity Capture-MS), KLRF1 (Synthetic Lethality), KLRF1 (Two-hybrid), KLRF1 (Proximity Label-MS), REEP6 (Affinity Capture-MS)

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: 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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	5
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

857 predictions. Top by Δscore:

Variant	Effect	Δscore
12:9844412:CCCTA:C	acceptor_loss	1.0000
12:9844413:CCTA:C	acceptor_loss	1.0000
12:9844416:A:AG	acceptor_gain	1.0000
12:9844417:G:GC	acceptor_loss	1.0000
12:9844417:G:GG	acceptor_gain	1.0000
12:9827627:AAGGT:A	donor_loss	0.9900
12:9827628:AGGTA:A	donor_loss	0.9900
12:9827630:G:GA	donor_loss	0.9900
12:9832509:A:AG	acceptor_gain	0.9900
12:9833215:A:AG	acceptor_gain	0.9900
12:9827631:T:G	donor_loss	0.9800
12:9832314:A:AG	acceptor_gain	0.9800
12:9832315:G:GG	acceptor_gain	0.9800
12:9832415:G:GG	donor_gain	0.9800
12:9833299:CAAG:C	acceptor_gain	0.9800
12:9833301:A:T	acceptor_gain	0.9800
12:9842431:GAT:G	donor_gain	0.9800
12:9844417:GA:G	acceptor_gain	0.9800
12:9844417:GATT:G	acceptor_gain	0.9800
12:9832313:CAGA:C	acceptor_gain	0.9700
12:9832410:GTTGG:G	donor_gain	0.9700
12:9832413:GG:G	donor_gain	0.9700
12:9832414:GG:G	donor_gain	0.9700
12:9832508:C:G	acceptor_gain	0.9700
12:9833298:TCAA:T	acceptor_gain	0.9700
12:9833302:G:T	acceptor_gain	0.9600
12:9842300:A:AG	acceptor_gain	0.9600
12:9842301:G:GG	acceptor_gain	0.9600
12:9827630:G:GG	donor_gain	0.9500
12:9832309:GTCTC:G	acceptor_loss	0.9500

AlphaMissense

1529 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:9841882:G:C	W135C	0.992
12:9841882:G:T	W135C	0.992
12:9841903:T:G	C142W	0.991
12:9841889:A:C	S138R	0.990
12:9841891:T:A	S138R	0.990
12:9841891:T:G	S138R	0.990
12:9842404:G:C	W186C	0.989
12:9842404:G:T	W186C	0.989
12:9842362:G:C	W172C	0.988
12:9842362:G:T	W172C	0.988
12:9842370:T:C	L175P	0.987
12:9842398:G:C	W184C	0.986
12:9842398:G:T	W184C	0.986
12:9844509:T:A	W227R	0.985
12:9844509:T:C	W227R	0.985
12:9844515:T:A	C229S	0.985
12:9844516:G:C	C229S	0.985
12:9841901:T:A	C142S	0.984
12:9841902:G:A	C142Y	0.984
12:9841902:G:C	C142S	0.984
12:9844517:T:G	C229W	0.984
12:9842366:G:T	G174W	0.981
12:9844516:G:A	C229Y	0.980
12:9841901:T:C	C142R	0.979
12:9842360:T:A	W172R	0.979
12:9842360:T:C	W172R	0.979
12:9844456:C:A	A209D	0.977
12:9842396:T:A	W184R	0.975
12:9842396:T:C	W184R	0.975
12:9844452:T:A	C208S	0.975

dbSNP variants (sampled 300 via entrez): RS1000095648 (12:9834102 T>TG), RS1000249516 (12:9798999 GA>G,GAA,GAAA), RS1000299093 (12:9798418 C>T), RS1000303076 (12:9814648 G>A), RS1000311033 (12:9839563 A>G), RS1000325595 (12:9804689 G>A), RS1000346354 (12:9811499 G>C), RS1000369349 (12:9821173 C>T), RS1000445254 (12:9804908 G>A,T), RS1000447826 (12:9833750 CTTAT>C), RS1000505911 (12:9817449 C>T), RS1000621445 (12:9798702 C>A,G,T), RS1000644838 (12:9808995 T>C), RS1000779881 (12:9838330 A>C), RS1000792141 (12:9802916 C>T)

Disease associations

OMIM: gene MIM:605029 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010322_3	Levodopa wearing off effect (time symptoms uncontrolled) in Parkinson’s disease (response to zonisamide)	5.000000e-06
GCST010725_46	Malaria	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010747	response to levodopa
EFO:0010749	motor function measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	affects methylation, affects acetylation	1
di-n-butylphosphoric acid	affects expression	1
monomethylarsonous acid	affects acetylation, affects methylation	1
Acetaminophen	affects cotreatment, decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects expression	1
Benzo(a)pyrene	affects methylation	1
Choline	affects expression	1
Dietary Carbohydrates	affects cotreatment, decreases expression	1
Lipopolysaccharides	decreases expression	1
Nickel	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases methylation	1
Simvastatin	decreases expression	1

Clinical trials (associated diseases)

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