KLRF2

Summary

KLRF2 (killer cell lectin like receptor F2, HGNC:37646) is a protein-coding gene on chromosome 12p13.31, encoding Killer cell lectin-like receptor subfamily F member 2 (D3W0D1). C-type lectin-like receptor involved in natural killer cell mediated cytotoxicity and cytokine secretion in keratinocytes via its interaction with CLEC2A.

Enables protein homodimerization activity. Predicted to be involved in natural killer cell degranulation and positive regulation of cytokine production. Predicted to act upstream of or within natural killer cell activation and positive regulation of natural killer cell mediated cytotoxicity. Located in plasma membrane.

Source: NCBI Gene 100431172 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• MANE Select transcript: NM_001190765

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:37646
Approved symbol	KLRF2
Name	killer cell lectin like receptor F2
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	NKp65
Ensembl gene	ENSG00000256797
Ensembl biotype	protein_coding
OMIM	618814
Entrez	100431172

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000535540

RefSeq mRNA: 1 — MANE Select: NM_001190765 NM_001190765

CCDS: CCDS53743

Canonical transcript exons

ENST00000535540 — 6 exons

Exon	Start	End
ENSE00002209212	9893020	9893168
ENSE00002213458	9893429	9893541
ENSE00002235247	9881489	9881665
ENSE00002289383	9895689	9895833
ENSE00002322795	9884934	9885032
ENSE00002323090	9888733	9888780

Expression profiles

Bgee: expression breadth broad, 45 present calls, max score 86.84.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0634 / max 31.4015, expressed in 20 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124102	0.0527	19
124103	0.0107	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.84	gold quality
skin of leg	UBERON:0001511	72.38	gold quality
zone of skin	UBERON:0000014	71.49	gold quality
skin of abdomen	UBERON:0001416	70.17	gold quality
duodenum	UBERON:0002114	59.49	gold quality
endometrium	UBERON:0001295	59.46	gold quality
granulocyte	CL:0000094	54.24	gold quality
rectum	UBERON:0001052	48.13	gold quality
lymph node	UBERON:0000029	47.72	gold quality
placenta	UBERON:0001987	47.54	gold quality
mucosa of transverse colon	UBERON:0004991	44.15	silver quality
gall bladder	UBERON:0002110	42.59	gold quality
tonsil	UBERON:0002372	42.45	gold quality
lower esophagus mucosa	UBERON:0035834	40.83	silver quality
leukocyte	CL:0000738	39.84	gold quality
monocyte	CL:0000576	39.77	gold quality
apex of heart	UBERON:0002098	39.74	silver quality
smooth muscle tissue	UBERON:0001135	38.24	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
small intestine	UBERON:0002108	35.27	gold quality
bone marrow	UBERON:0002371	35.09	silver quality
fallopian tube	UBERON:0003889	34.67	gold quality
muscle tissue	UBERON:0002385	34.43	silver quality
vermiform appendix	UBERON:0001154	34.10	silver quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
small intestine Peyer’s patch	UBERON:0003454	33.19	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.59

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 5)

• Keratinocytes express KACL and are capable of stimulating NKp65-expressing cells in a KACL-dependent manner. (PMID:20194751)
• structure explains the exceptionally high affinity of the NKp65-KACL interaction compared with other cell-cell interaction pairs, which may compensate for the monomeric nature of NKp65 to achieve cell activation (PMID:23803857)
• Key residues at the membrane-distal surface of KACL, but not glycosylation, determine the functional interaction of the keratinocyte-specific C-type lectin-like receptor KACL with its high-affinity receptor NKp65 (PMID:25510854)
• NKp65 utilizes a hemi-immunoreceptor tyrosine-based activation motif -like motif for cellular activation that requires Syk, although Syk appears not to be recruited to NKp65. (PMID:28082678)
• The activating receptor NKp65 is selectively expressed by human ILC3 and demarcates ILC3 from mature NK cells. (PMID:38072999)

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), 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), CLEC5A (ENSG00000258227)

Protein

Protein identifiers

Killer cell lectin-like receptor subfamily F member 2 — D3W0D1 (reviewed: D3W0D1)

Alternative names: Activating coreceptor NKp65

All UniProt accessions (1): D3W0D1

UniProt curated annotations — full annotation on UniProt →

Function. C-type lectin-like receptor involved in natural killer cell mediated cytotoxicity and cytokine secretion in keratinocytes via its interaction with CLEC2A. Triggers degranulation in a SYK-dependent manner and stimulates SYK phosphotyrosinylation without recruiting SYK directly.

Subunit / interactions. Homodimer; non-disulfide-linked. Interacts with CLEC2A.

Subcellular location. Cell membrane.

Post-translational modifications. N-glycosylated.

RefSeq proteins (1): NP_001177694* (*=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 (29 total): strand 11, disulfide bond 3, helix 3, turn 3, topological domain 2, glycosylation site 2, chain 1, mutagenesis site 1, transmembrane region 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4IOP	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-D3W0D1-F1	82.66	0.62

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 (3): 172–185, 78–89, 106–193

Glycosylation sites (2): 67, 202

Mutagenesis-validated functional residues (1):

Position	Phenotype
7	loss of function.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 33 (showing top): GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_EXOCYTOSIS, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, GOBP_CYTOKINE_PRODUCTION, GOBP_SECRETION, GOBP_NATURAL_KILLER_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_NATURAL_KILLER_CELL_MEDIATED_IMMUNITY, GOBP_NATURAL_KILLER_CELL_ACTIVATION, GOBP_IMMUNE_EFFECTOR_PROCESS, GOBP_CELL_KILLING

GO Biological Process (2): positive regulation of cytokine production (GO:0001819), natural killer cell degranulation (GO:0043320)

GO Molecular Function (3): carbohydrate binding (GO:0030246), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
natural killer cell activation involved in immune response	1
natural killer cell mediated cytotoxicity	1
leukocyte degranulation	1
identical protein binding	1
protein dimerization activity	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

134 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLRF2	CLEC2A	Q6UVW9	994
KLRF2	CLEC2B	Q92478	726
KLRF2	CLEC1B	Q9P126	512
KLRF2	HCST	Q9UBK5	427
KLRF2	FCAR	P24071	418
KLRF2	DCLK3	Q9C098	400
KLRF2	NCR3	O14931	349
KLRF2	NCR2	O95944	349
KLRF2	CD226	Q15762	335
KLRF2	SLAMF6	Q96DU3	312
KLRF2	NCR1	O76036	311
KLRF2	SLAMF7	Q9NQ25	259
KLRF2	CLEC2D	Q9UHP7	252
KLRF2	CD69	Q07108	245
KLRF2	HLA-DMA	P28067	224
KLRF2	SYK	P43405	224

IntAct

7 interactions, top by confidence:

A	B	Type	Score
KLRF2	CLEC2A	psi-mi:“MI:0407”(direct interaction)	0.740
CLEC2A	KLRF2	psi-mi:“MI:0407”(direct interaction)	0.740
CLEC2A	KLRF2	psi-mi:“MI:0915”(physical association)	0.740
KLRF2	KLRF2	psi-mi:“MI:0407”(direct interaction)	0.440

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

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

852 predictions. Top by Δscore:

Variant	Effect	Δscore
12:9893211:GCT:G	donor_gain	1.0000
12:9893537:GAATT:G	donor_gain	1.0000
12:9893542:G:GG	donor_gain	1.0000
12:9895687:A:C	acceptor_loss	1.0000
12:9888722:A:AG	acceptor_gain	0.9900
12:9888722:ACT:A	acceptor_gain	0.9900
12:9893203:G:GT	donor_gain	0.9900
12:9893204:A:T	donor_gain	0.9900
12:9895687:A:AG	acceptor_gain	0.9900
12:9895687:AG:A	acceptor_gain	0.9900
12:9895688:G:A	acceptor_gain	0.9900
12:9895688:G:GA	acceptor_gain	0.9900
12:9895688:GGT:G	acceptor_gain	0.9900
12:9881661:TAAAG:T	donor_loss	0.9800
12:9881662:AAAG:A	donor_loss	0.9800
12:9881663:AAG:A	donor_loss	0.9800
12:9881664:AGG:A	donor_loss	0.9800
12:9881666:G:T	donor_loss	0.9800
12:9881667:T:A	donor_loss	0.9800
12:9888723:C:G	acceptor_gain	0.9800
12:9893116:ATT:A	donor_gain	0.9800
12:9893127:C:G	donor_gain	0.9800
12:9893165:GCTG:G	donor_gain	0.9800
12:9893187:GATC:G	donor_gain	0.9800
12:9893428:GGA:G	acceptor_gain	0.9800
12:9893538:AATTG:A	donor_loss	0.9800
12:9893539:ATTGT:A	donor_loss	0.9800
12:9893540:TTGTG:T	donor_loss	0.9800
12:9893541:TGTGA:T	donor_loss	0.9800
12:9893542:G:A	donor_loss	0.9800

AlphaMissense

1388 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:9893099:G:C	W99C	0.968
12:9893099:G:T	W99C	0.968
12:9893470:G:C	W136C	0.960
12:9893470:G:T	W136C	0.960
12:9893512:G:C	W150C	0.950
12:9893512:G:T	W150C	0.950
12:9893432:T:C	F124L	0.949
12:9893434:C:A	F124L	0.949
12:9893434:C:G	F124L	0.949
12:9895790:A:C	Q194P	0.948
12:9893048:G:C	W82C	0.947
12:9893048:G:T	W82C	0.947
12:9893468:T:A	W136R	0.941
12:9893468:T:C	W136R	0.941
12:9893133:G:C	A111P	0.940
12:9893067:T:A	C89S	0.938
12:9893068:G:C	C89S	0.938
12:9895786:T:A	C193S	0.925
12:9895787:G:C	C193S	0.925
12:9893118:T:A	C106S	0.924
12:9893119:G:C	C106S	0.924
12:9893140:T:C	L113S	0.916
12:9893506:G:C	W148C	0.913
12:9893506:G:T	W148C	0.913
12:9893034:T:A	C78S	0.912
12:9893035:G:C	C78S	0.912
12:9895727:C:A	A173D	0.912
12:9893120:T:G	C106W	0.911
12:9895723:T:A	C172S	0.908
12:9895724:G:C	C172S	0.908

dbSNP variants (sampled 300 via entrez): RS1000115796 (12:9894491 C>T), RS1000453609 (12:9886165 T>G), RS1000486619 (12:9896164 C>A), RS1000660993 (12:9891531 T>C), RS1000700205 (12:9890686 A>G), RS1000713742 (12:9884087 G>C,T), RS1001170086 (12:9894936 A>G,T), RS1001862587 (12:9884751 C>T), RS1002031800 (12:9890377 G>A), RS1002038153 (12:9884936 T>A,G), RS1002323706 (12:9884540 T>C), RS1002523746 (12:9893549 G>T), RS1002683209 (12:9880571 A>G), RS1002697375 (12:9888210 G>C), RS1002702228 (12:9888135 A>G)

Disease associations

OMIM: gene MIM:618814 | 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
GCST010725_46	Malaria	1.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

Clinical trials (associated diseases)

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