KIR2DS4

Summary

KIR2DS4 (killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 4 (gene/pseudogene), HGNC:6336) is a protein-coding gene on chromosome 19q13.42, encoding Killer cell immunoglobulin-like receptor 2DS4 (P43632). Receptor on natural killer (NK) cells for HLA-C alleles.

Killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer cells and subsets of T cells. The KIR genes are polymorphic and highly homologous and they are found in a cluster on chromosome 19q13.4 within the 1 Mb leukocyte receptor complex (LRC). The gene content of the KIR gene cluster varies among haplotypes, although several “framework” genes are found in all haplotypes (KIR3DL3, KIR3DP1, KIR3DL4, KIR3DL2). The KIR proteins are classified by the number of extracellular immunoglobulin domains (2D or 3D) and by whether they have a long (L) or short (S) cytoplasmic domain. KIR proteins with the long cytoplasmic domain transduce inhibitory signals upon ligand binding via an immune tyrosine-based inhibitory motif (ITIM), while KIR proteins with the short cytoplasmic domain lack the ITIM motif and instead associate with the TYRO protein tyrosine kinase binding protein to transduce activating signals. The ligands for several KIR proteins are subsets of HLA class I molecules; thus, KIR proteins are thought to play an important role in regulation of the immune response.

Source: NCBI Gene 3809 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 37 total

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6336
Approved symbol	KIR2DS4
Name	killer cell immunoglobulin like receptor, two Ig domains and short cytoplasmic tail 4 (gene/pseudogene)
Location	19q13.42
Locus type	gene with protein product
Status	Approved
Aliases	cl-39, KKA3, nkat8, CD158I
Ensembl gene	ENSG00000221957
Ensembl biotype	protein_coding
OMIM	604955
Entrez	3809

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding_LoF

ENST00000339924, ENST00000391729

RefSeq mRNA: 2 — MANE Select: None NM_001281971, NM_001281972

Canonical transcript exons

ENST00000339924 — 8 exons

Exon	Start	End
ENSE00001367412	54839428	54839699
ENSE00002348042	54832676	54832798
ENSE00002358728	54847902	54848569
ENSE00002465770	54842868	54842918
ENSE00002469527	54835079	54835114
ENSE00002514306	54837576	54837875
ENSE00002520395	54847184	54847288
ENSE00002524958	54847751	54847803

Expression profiles

Bgee: expression breadth broad, 63 present calls, max score 84.42.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	84.42	silver quality
granulocyte	CL:0000094	82.85	gold quality
olfactory bulb	UBERON:0002264	75.62	gold quality
type B pancreatic cell	CL:0000169	73.39	gold quality
diaphragm	UBERON:0001103	70.56	gold quality
tongue squamous epithelium	UBERON:0006919	70.37	gold quality
blood	UBERON:0000178	69.16	gold quality
hair follicle	UBERON:0002073	67.69	gold quality
epithelial cell of pancreas	CL:0000083	66.66	gold quality
nasal cavity epithelium	UBERON:0005384	66.02	gold quality
cervix squamous epithelium	UBERON:0006922	66.01	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	65.74	gold quality
decidua	UBERON:0002450	65.68	gold quality
mucosa of paranasal sinus	UBERON:0005030	64.93	gold quality
mammary duct	UBERON:0001765	64.53	gold quality
cervix epithelium	UBERON:0004801	64.00	gold quality
epithelium of mammary gland	UBERON:0003244	63.74	gold quality
buccal mucosa cell	CL:0002336	63.47	gold quality
bone marrow cell	CL:0002092	62.83	silver quality
quadriceps femoris	UBERON:0001377	62.46	gold quality
gluteal muscle	UBERON:0002000	62.22	gold quality
triceps brachii	UBERON:0001509	62.19	gold quality
vastus lateralis	UBERON:0001379	61.93	gold quality
medial globus pallidus	UBERON:0002477	61.50	gold quality
left ventricle myocardium	UBERON:0006566	61.02	gold quality
CA1 field of hippocampus	UBERON:0003881	61.01	gold quality
cardia of stomach	UBERON:0001162	60.55	gold quality
superficial temporal artery	UBERON:0001614	60.55	gold quality
pancreatic ductal cell	CL:0002079	60.47	silver quality
ileal mucosa	UBERON:0000331	59.96	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.38

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• KIR2DS4 interacts with a non-class-I MHC protein on melanomas. This interaction is both specific & functional. Site-directed mutagenesis shows that the AAs involved in recognizing this novel ligand are different from those interacting with HLA-Cw4. (PMID:15265913)
• KIR 2DS4 may be a risk factor for susceptibility to RA in Taiwan. (PMID:16641046)
• The presence of KIR1D in the absence of KIR2DS4*001 was detected significantly more frequently in Chronic Myeloid Leukemia (PMID:18463675)
• Findings in HCV-infected and non-infected IDUs suggest an important role for KIRs (KIR2DL2 and KIR2DL3) with group HLA-C1 molecules, in the presence of activating KIR2DS4, in protection from HCV infection. (PMID:19552960)
• Determination of the crystallographic structure of KIR2DS4 shows two major differences from KIR2DL: displacement of contact loop L2 and altered bonding potential because of the substitutions at positions 71 and 72. (PMID:19858347)
• Data revealed that the trend of parasitic positive individuals to be KIR3DL1/KIR3DS1 heterozygous in pair with KIR2DS4 nondeleted variants in a set of KIR genes inheritable as the AB genotypes. (PMID:19859704)
• significant association of full-length KIR2DS4 or KIR2DL1/3DL1 expression with the occurrence of acute graft vs host disease in hematopoietic stem cell transplantation (PMID:20062104)
• KIR2DS4*001, the only allele of KIR2DS4 known to encode a functional activating receptor, was associated with relatively high viral load for HIV-1 and with accelerated transmission of HIV-1 to cohabiting seronegative partners. (PMID:21216870)
• Data indicate that the increased frequency of CD8(+) effector-memory T cells with activating NKR KIR2DS4, NKG2C and NKG2D, and cytotoxicity toward hematopoietic cell lines suggests involvement in bone marrow failure and clonal expansion in PNH. (PMID:21554925)
• The CMV seropositivity of donors was not associated with activating KIR expression, and donor null expression in those with the KIR2DS2 or KIR2DS4 genotype was not predictive for CMV reactivation in the recipient. (PMID:21596150)
• KIR1D/KIR1D might play a key role in Treponema pallidum infection in Chinese Han population that belongs to KIR gene haplotype A. (PMID:22128817)
• in response to HCT therapy, the activating receptors are also enhanced by a process that increases the number of unmethylated sites present on KIR2DS2/4 promoters. (PMID:22939905)
• Results suggest a protective role of KIR2DS5 in graft rejection and an association of KIR2DS4 with kidney rejection, particularly in recipients with glomerulonephritis. (PMID:23028591)
• Our data revealed a unique contribution of activating KIRs (KIR2DS4, KIR2DS2, or KIR3DS1), in addition to NKG2C, in the expansion of human natural killer cells. (PMID:23325834)
• Data indicate that positive linkage disequilibrium was observed between KIR3DL1, 2DL1, 2DL3 and 2DS4 which is consistent with the associations between the constituents of A haplotypes. (PMID:23354323)
• lower genotype frequency in children with systemic juvenile idiopathic arthritis (PMID:24112428)
• Possession of the functional and non-functional KIR2DS4 isoforms in the mother and the fetus determines the risk of the vertical HIV-1 transmission. (PMID:24239756)
• Response of rheumatoid arthritis patients with medium ESR values to methotrexate treatment may be dependent on the full-length KIR2DS4 gene. (PMID:25069714)
• Study shows KIR3DL1 and KIR2DS4 gene variants are linked and that the gene KIR2DS5 is only present in the telomeric half of the KIR locus. Study revealed novel insights in the highly organized distribution of KIR genes. (PMID:25503311)
• These results highlight the impact of population allele frequency on viral control and identify a novel association between HLA-C04 : 01 in combination with KIR2DS4f and uncontrolled HIV infection. (PMID:25715101)
• KIR2DS4del presence in patients was associated with severity of endometriosis, which, due to strong negative linkage disequilibrium, may suggest an indirect effect of KIR2DS5 absence (PMID:25724317)
• KIR2DS4 can induce the uptake of CCR7 by KIR2DS4(+) NKG2A(+) natural killer cell clones after interacting with CCR7(+) target cells expressing HLA-Cw4 and HLA-Cw6 alleles. (PMID:25961063)
• genetic association study in population in Eastern India: Data suggest that interactions between KIRs (KIR2DL2, KIR2DS4, KIR2DL3) and HLA ligands (HLAC1, HLAC2) contribute significantly toward susceptibility and protection toward type 1 diabetes. (PMID:26031759)
• genetic polymorphism is associated with the course of Hepatitis C virus infection and the response to therapy (PMID:26206121)
• Collectively, our data suggest that the KIR 2DS4/1D allelic variance is associated with the outcome of sibling-related HLA-matched HSCT, and that donor subclassification of KIR 2DS4/1D alleles should be considered in this setting. (PMID:26476204)
• Type 1 pediatric autoimmune hepatitis patients show increased frequency of KIR2DS4-Full Length, which in combination with HLA-DRB1*1301 revealed a strong synergistic effect. Adult autoimmune hepatitis cases have shown a weaker increased frequency of KIR2DS4-FL, a lack of synergistic effect with HLA class II antigens. (PMID:26890333)
• Our findings suggest that KIR2DS4*00101 may offer a molecular biomarker to identify intrinsically milder forms of glioblastoma (PMID:27406829)
• KIR2DS4, KIR2DS1, and some alleles of KIR2DS5 contribute to successful pregnancy suggests that activation of uNK cells by KIR binding to HLA-C is a generic mechanism promoting trophoblast invasion into the decidua. (PMID:27815424)
• KIR 2D (L1, L3, L4, S4) and KIR 3DL1 expression was correlated with poor prognosis in non-small cell lung carcinoma patients. (PMID:27893413)
• this study shows that the expression of full-length KIR2DS4 allele variants may contribute to a worse clinical outcome after hematopoietic stem cell transplantation (PMID:27998801)
• Data indicate the allelic diversity of KIR2DS4 proteni among ethnic Hans from southern China, which may provide data for transplantation as well as studies on KIR-associated disease and evolution. (PMID:28186587)
• KIR2DS4 was associated with significant reduced incidence of relapse of hematological malignancies after hematopoietic stem cell transplantation from matched sibling (PMID:28993188)
• The higher frequencies of KIR3DS1-Bw4 and homozygotic KIR2DS4- in patients compared with controls suggest they confer susceptibility to polycystic ovary syndrome. A lower frequency of KIR2DS4-full was observed in patients. (PMID:30099219)
• Promoter methylation decreased and gene expression increased for KIR2DS4 after acute exercise. Chronic exercise resulted in a minor decrease of DNA methylation and did not alter gene expression. (PMID:30508863)
• KIR2DS4 has a strong preference for rare peptides carrying a Trp at position 8 (p8) of 9-mer peptides bound to HLA-C*05:01. The complex of a peptide bound to HLA-C*05:01 with a Trp at p8 was sufficient for activation of primary KIR2DS4+ NK cells, independent of activation by other receptors and of prior NK cell licensing. Study predicts that over 1,000 bacterial species could activate NK cells through KIR2DS4. (PMID:31138701)
• In head and neck squamous cell carcinoma (HNSCC), KIR2DL2 is positively while KIR2DS4 is negatively associated with advanced stage. The higher proportion of LNM in carriers of KIR2DL2 and carriers of 5 iKIRs, suggested that inhibitory KIRs are associated with metastatic risk (PMID:31751561)
• Positive association of Bx genotype, KIR2L5, KIR2DS5 and full-length KIR2DS4 with the risk of meningioma. (PMID:31899050)
• Natural killer cell receptor variants and chronic hepatitis B virus infection in the Vietnamese population. (PMID:32422377)
• The impact of donor full-length KIR2DS4 in the development of acute and chronic GVHD after unrelated allogeneic HSCT. (PMID:32594584)
• Association of KIR gene polymorphisms with COVID-19 disease. (PMID:34929414)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Kir3dl1	ENSMUSG00000031424
mus_musculus	Kir3dl2	ENSMUSG00000057439
rattus_norvegicus	Kir3dl1	ENSRNOG00000027843

Paralogs (25): GP6 (ENSG00000088053), LILRB1 (ENSG00000104972), LILRA1 (ENSG00000104974), LILRB5 (ENSG00000105609), A1BG (ENSG00000121410), KIR2DL1 (ENSG00000125498), LILRB2 (ENSG00000131042), IGSF1 (ENSG00000147255), LAIR2 (ENSG00000167618), KIR3DL1 (ENSG00000167633), OSCAR (ENSG00000170909), FCAR (ENSG00000186431), LILRB4 (ENSG00000186818), LILRA5 (ENSG00000187116), KIR2DL4 (ENSG00000189013), VSTM1 (ENSG00000189068), NCR1 (ENSG00000189430), LILRB3 (ENSG00000204577), LILRA4 (ENSG00000239961), LILRA2 (ENSG00000239998), KIR3DL2 (ENSG00000240403), KIR3DL3 (ENSG00000242019), KIR2DL3 (ENSG00000243772), LILRA6 (ENSG00000244482), TARM1 (ENSG00000248385)

Protein

Protein identifiers

Killer cell immunoglobulin-like receptor 2DS4 — P43632 (reviewed: P43632)

Alternative names: CD158 antigen-like family member I, Natural killer-associated transcript 8, P58 natural killer cell receptor clones CL-39/CL-17

All UniProt accessions (0):

UniProt curated annotations — full annotation on UniProt →

Function. Receptor on natural killer (NK) cells for HLA-C alleles. Does not inhibit the activity of NK cells.

Subunit / interactions. Interacts with HLA-F; this interaction is direct.

Subcellular location. Cell membrane.

Similarity. Belongs to the immunoglobulin superfamily.

RefSeq proteins (2): NP_001268900, NP_001268901 (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR013151	Immunoglobulin_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050412	Ig-like_Receptors_ImmuneReg	Family

Pfam: PF00047

UniProt features (42 total): strand 16, sequence variant 10, glycosylation site 5, disulfide bond 2, topological domain 2, domain 2, region of interest 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3H8N	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43632-F1	82.02	0.60

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): 49–100, 149–198

Glycosylation sites (5): 84, 144, 178, 211, 67

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2172127	DAP12 interactions

MSigDB gene sets: 26 (showing top): CHOI_ATL_ACUTE_STAGE, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GNF2_IL2RB, GOMF_SIGNALING_RECEPTOR_BINDING, KEGG_ANTIGEN_PROCESSING_AND_PRESENTATION, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, HAHTOLA_SEZARY_SYNDROM_DN, GOMF_MHC_PROTEIN_BINDING, GOBP_IMMUNE_RESPONSE_REGULATING_SIGNALING_PATHWAY, GOBP_IMMUNE_RESPONSE_INHIBITING_SIGNAL_TRANSDUCTION, RATTENBACHER_BOUND_BY_CELF1, GOMF_MHC_CLASS_IB_PROTEIN_BINDING, REACTOME_DAP12_INTERACTIONS, GOMF_IMMUNE_RECEPTOR_ACTIVITY

GO Biological Process (1): immune response-regulating signaling pathway (GO:0002764)

GO Molecular Function (1): MHC class Ib protein binding (GO:0023029)

GO Cellular Component (1): plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	1
regulation of immune response	1
MHC protein binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

23 interactions, top by confidence:

A	B	Type	Score
KIR2DS4	HLA-F	psi-mi:“MI:0915”(physical association)	0.670
KIR2DS4	HLA-F	psi-mi:“MI:0407”(direct interaction)	0.670
KIR2DS4	HLA-C	psi-mi:“MI:0407”(direct interaction)	0.440
KIR2DS4	HLA-A	psi-mi:“MI:0407”(direct interaction)	0.440
KIR2DS4	HLA-B	psi-mi:“MI:0407”(direct interaction)	0.440
KIR2DS4	GP6	psi-mi:“MI:0915”(physical association)	0.400
KIR2DS4	LILRB2	psi-mi:“MI:0915”(physical association)	0.400
KIR2DS4	SIGLEC6	psi-mi:“MI:0915”(physical association)	0.400

ESM2 similar proteins: A0A0B4J1G0, A0A0B4J1L0, A0A0G2KBC9, A1YIY0, A8MTB9, B6A8R8, C0HJX2, C0HJX3, E2RP87, H0VDZ8, P08637, P09326, P12314, P23505, P26151, P43626, P43627, P43628, P43631, P43632, P83555, P83556, Q01965, Q13291, Q14952, Q14953, Q14954, Q28942, Q2YHT5, Q61400, Q61450, Q640U3, Q68EV1, Q68SN8, Q6UX41, Q6UXE8, Q6UY09, Q6XJV4, Q6XPU4, Q7TST0

Diamond homologs: A0A0G2KBC9, A6NI73, B6A8R8, C0HJX2, C0HJX3, D3ZQX2, O75019, O75022, O75023, O76036, P0C191, P0C1X9, P24071, P43626, P43627, P43628, P43629, P43630, P43631, P43632, P59901, P83555, P83556, P97484, Q14943, Q14952, Q14953, Q14954, Q61450, Q64281, Q6GTX8, Q6ISS4, Q6PI73, Q7TQA1, Q863H2, Q8C567, Q8IYS5, Q8MJZ2, Q8MJZ7, Q8N109

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	11
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

912 predictions. Top by Δscore:

Variant	Effect	Δscore
19:54832799:G:GA	donor_loss	1.0000
19:54832800:T:A	donor_loss	1.0000
19:54847179:TCCA:T	acceptor_loss	1.0000
19:54847181:CAGGT:C	acceptor_loss	1.0000
19:54847182:A:AT	acceptor_loss	1.0000
19:54847285:AAAA:A	donor_gain	1.0000
19:54847285:AAAAG:A	donor_loss	1.0000
19:54847286:AAA:A	donor_gain	1.0000
19:54847286:AAAGT:A	donor_loss	1.0000
19:54847287:AA:A	donor_gain	1.0000
19:54847287:AAGTA:A	donor_loss	1.0000
19:54847288:AGTAA:A	donor_loss	1.0000
19:54847289:G:GG	donor_gain	1.0000
19:54847289:GTAA:G	donor_loss	1.0000
19:54847290:TAAGT:T	donor_loss	1.0000
19:54832795:GTTG:G	donor_gain	0.9900
19:54832799:G:GG	donor_gain	0.9900
19:54837697:G:GT	donor_gain	0.9900
19:54837697:G:T	donor_gain	0.9900
19:54837792:G:GT	donor_gain	0.9900
19:54847182:A:AG	acceptor_gain	0.9900
19:54847183:G:GG	acceptor_gain	0.9900
19:54847183:GGT:G	acceptor_gain	0.9900
19:54847183:GGTA:G	acceptor_gain	0.9900
19:54847183:GGTAA:G	acceptor_gain	0.9900
19:54847284:AAAAA:A	donor_gain	0.9900
19:54847680:T:A	acceptor_gain	0.9900
19:54847748:CAGA:C	acceptor_loss	0.9900
19:54847749:A:AG	acceptor_gain	0.9900
19:54847750:G:GG	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000973765 (19:54847209 G>A,T), RS1001149346 (19:54782731 T>G), RS1001479341 (19:54847003 G>A,T), RS1001576466 (19:54841191 T>C), RS1002227919 (19:54784309 C>T), RS1002510093 (19:54831661 T>C), RS1002710694 (19:54837307 A>G,T), RS1002905831 (19:54837226 G>A,T), RS1003647835 (19:54834355 G>A), RS1004045109 (19:54783521 A>C), RS1004439534 (19:54838616 G>A,C), RS1004794232 (19:54838977 T>C,G), RS1004930486 (19:54844577 T>G), RS1005019890 (19:54782346 A>G,T), RS1005052437 (19:54782201 A>G)

Disease associations

OMIM: gene MIM:604955 | 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
GCST90002388_382	Lymphocyte count	3.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation	1
(+)-JQ1 compound	decreases expression	1
Bortezomib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Azacitidine	increases expression	1
Cadmium	decreases expression	1
Valproic Acid	increases methylation	1
Cyclosporine	increases methylation	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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