KIR2DL4

Summary

KIR2DL4 (killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 4, HGNC:6332) is a protein-coding gene on chromosome 19q13.42, encoding Killer cell immunoglobulin-like receptor 2DL4 (Q99706). Receptor for non-classical major histocompatibility class Ib HLA-G molecules.

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. This gene is one of the “framework” loci that is present on all haplotypes. Alternate alleles of this gene are represented on multiple alternate reference loci (ALT_REF_LOCs). Alternative splicing results in multiple transcript variants, some of which may not be annotated on the primary reference assembly.

Source: NCBI Gene 3805 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 77 total
• MANE Select transcript: NM_001080770

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6332
Approved symbol	KIR2DL4
Name	killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 4
Location	19q13.42
Locus type	gene with protein product
Status	Approved
Aliases	103AS, 15.212, CD158D
Ensembl gene	ENSG00000189013
Ensembl biotype	protein_coding
OMIM	604945
Entrez	3805

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000345540, ENST00000346587, ENST00000357494, ENST00000359085, ENST00000396289, ENST00000396293, ENST00000463062, ENST00000486965, ENST00000861932

RefSeq mRNA: 2 — MANE Select: NM_001080770 NM_001080770, NM_001080772

CCDS: CCDS42619, CCDS42620

Canonical transcript exons

ENST00000345540 — 7 exons

Exon	Start	End
ENSE00002526938	54808833	54808883
ENSE00003530314	54813690	54813742
ENSE00003543375	54803891	54803926
ENSE00003577021	54805951	54806244
ENSE00003631426	54813842	54814517
ENSE00003632673	54804793	54805077
ENSE00003668813	54803610	54803691

Expression profiles

Bgee: expression breadth ubiquitous, 116 present calls, max score 86.97.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6005 / max 162.5994, expressed in 125 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177551	0.2730	86
177553	0.2594	46
177554	0.0467	13
177552	0.0214	5

Top tissues by expression

269 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	86.97	gold quality
spleen	UBERON:0002106	72.18	gold quality
tendon of biceps brachii	UBERON:0008188	69.18	silver quality
granulocyte	CL:0000094	69.06	gold quality
ileal mucosa	UBERON:0000331	67.23	silver quality
mucosa of transverse colon	UBERON:0004991	66.06	gold quality
buccal mucosa cell	CL:0002336	65.69	gold quality
blood	UBERON:0000178	64.78	gold quality
pancreatic ductal cell	CL:0002079	64.25	silver quality
frontal pole	UBERON:0002795	63.56	gold quality
Brodmann (1909) area 10	UBERON:0013541	63.16	gold quality
right lung	UBERON:0002167	62.27	gold quality
middle frontal gyrus	UBERON:0002702	62.17	gold quality
paraflocculus	UBERON:0005351	61.80	gold quality
tibialis anterior	UBERON:0001385	60.66	silver quality
gluteal muscle	UBERON:0002000	60.19	gold quality
triceps brachii	UBERON:0001509	60.14	gold quality
endometrium epithelium	UBERON:0004811	60.03	gold quality
rectum	UBERON:0001052	57.94	gold quality
deltoid	UBERON:0001476	57.57	gold quality
lateral globus pallidus	UBERON:0002476	56.88	gold quality
duodenum	UBERON:0002114	56.82	gold quality
colonic epithelium	UBERON:0000397	55.47	silver quality
vermiform appendix	UBERON:0001154	55.05	gold quality
caecum	UBERON:0001153	54.12	gold quality
leukocyte	CL:0000738	53.64	gold quality
transverse colon	UBERON:0001157	53.50	gold quality
upper lobe of left lung	UBERON:0008952	53.35	gold quality
upper leg skin	UBERON:0004262	52.99	silver quality
quadriceps femoris	UBERON:0001377	52.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.56

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DNMT1

Literature-anchored findings (GeneRIF, showing 40)

• Crosslinking of KIR2DL4 with a mAb induces interferon-gamma production, but not cytotoxicity, by resting NK cells in the absence of cytokines. (PMID:11489965)
• The single tyrosine-based inhibitory motif (ITIM)in the cytoplasmic domain of KIR2DL4 efficiently inhibits natural cytotoxicity responses and recruits SHP-2 protein tyrosine phosphatase (but not SHP-1) to the 2DL4 cytoplasmic domain in NK cells. (PMID:11994457)
• KIR2DL4 has the potential for both activating and inhibitory functions. (PMID:12055234)
• NK clones express both 2DL4 alleles and either one or both alleles of the clonally restricted KIR 3DL1 and 3DL2 genes. (PMID:12538663)
• All genotypes seen included genes for KIR2DL4. (PMID:12559621)
• NK cell receptor, KIR2DL4:HLA-G interaction is not essential for human reproduction. (PMID:12616484)
• The promoter for KIR2DL4 is expressed by all natural killer (NK) cell clones and drives reporter gene expression only in NK cells. (PMID:12794136)
• isolated 3 distinct KIR2DL4 allele clones in each individual with multiple copies of KIR3DL/S1; assumption that unequal crossover event occurred between differing KIR haplotypes resulting in the duplication of the 2DL4, 3DS1/3DL1 genes (PMID:12826375)
• KIR2DL4 transmembrane exon genotype influences both levels of membrane expression and activation of cytotoxic function. (PMID:12902476)
• Appropriate engagement of KIR2DL4 can selectively stimulate NK cells to elicit a strong IFN-gamma response, which has the potential to contribute significant biological benefits, but only in individuals capable of expressing this receptor. (PMID:14500636)
• Specific amplification of the D0 & D2 domains permit PCR discrimination of KIR2DL4 alleles & their frequencies in various cell lines and human populations. (PMID:14700593)
• 4.5% of the individuals of a Caucasoid population bear a recombinant allele of KIR3DP1, officially designed KIR3DP1*004, that associates tightly with gene duplications of KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1 (PMID:15580659)
• report that ILT2 receptor, ILT3 receptor, ILT4 receptor, and KIR2DL4 receptor expression is up-regulated by HLA-G histocompatibility antigen in antigen-presenting cells, natural killer cells, and T cells (PMID:15670976)
• evidence that FcepsilonRI-gamma (gamma) associates with 2DL4 to promote surface expression and provide signal transducing function. (PMID:15778339)
• an inhibitory element was identified in the KIR2DL4 promoter and an activating element was found in the KIR3DL3 promoter; AML-2 acts as a repressor of expression of both KIR2DL4 and KIR3DL3 in mature NK cells (PMID:15778373)
• KIR2DL4 alleles may explain the high frequency of this variation in the population. (PMID:15853895)
• KIR2DL4 was constitutively internalized into Rab5-positive compartments in NK cells via dynamin-dependent process. Chemokine secretion induced by KIR2DL4 transfection into 293T cells occurred only with recombinant forms of KIR2DL4 trafficked to endosomes. (PMID:16366734)
• New insights are provided into the mechanisms by which genetic polymorphism of the KIR2DL4 gene influences its expression. (PMID:17171757)
• 8 known KIR2DL4 alleles were observed in individuals involved in bone marrow transplantation; 3 new alleles, KIR2DL4*00203, *00502, *0080104, differering from known alleles at the nucleotide but not the protein sequence level were also identified (PMID:17610421)
• Three new alleles of KIR2DL4 have been identified, among those one allele showed alternatively spliced products. (PMID:18082267)
• Signaling pathways are specifically activated by engagement of killer receptor KIR2DL4 transmembrane association with the FcepsilonRI-gamma (FCER1G) receptor in natural killer (NK) cells. (PMID:18292514)
• Human leukocyte antigen-G, a ligand for the natural killer receptor KIR2DL4, is expressed by eutopic endometrium only in the menstrual phase. (PMID:18314122)
• Increased competency of T cells to express KIR2DL4 with aging is conferred by a selective increase in H3-Lys 4 dimethylation and limited DNA demethylation (PMID:18586981)
• The role of DNA methylation in regulating of the genes, KIR2DL2 and KIR2DL4, was characterized;these genes are normally suppressed in part by promoter methylation in non-expressing T cells. (PMID:18945643)
• Decreased KIR2DL4 expression in placenta may participate in the pathogenesis of pre-eclampsia. (PMID:19134329)
• Whereas 26% of the study population has a genotype corresponding to a lack of any functional membrane-bound form of the molecule, no association of the KIR2DL4 transmembrane alleles with susceptibility to MS was observed. (PMID:19304328)
• Cross-linking with anti-LILRB1 on CD14(+) macrophages or anti-KIR2DL4 on CD56(+) NK cells resulted in up-regulation of a small subset of mRNAs including those for IL-6, IL-8, and TNFalpha (PMID:19304799)
• Data showed that the CD70, perforin and KIR2DL4 promoters are demethylated in CD4(+)CD28(-) T cells, and that DNA methyltransferase 1 (Dnmt1) and Dnmt3a levels are decreased in this subset. (PMID:19394279)
• The study confirms that expression of KIR2DL4 by dNK is dependent on the 9A/10A polymorphism and that this polymorphism influences IFNgamma secretion by dNK cells. (PMID:19509110)
• Stimulatory molecule KIR2DL4 triggers interferon-gamma release by lupus T cells, and production is proportional to disease activity. (PMID:19675166)
• Expression patterns of KIR2DL4 were tightly linked with 9 and 10 poly-adenine polymorphism in exon 7. (PMID:19679155)
• KIR2DL4 itself is not associated with preeclampsia, but it may modulate the effect of HLA-G*0106 on risk for preeclampsia. (PMID:19700612)
• The sequential requirement for DNA-dependent protein kinase, Akt, and NF-kappaB in signaling by CD158d delineates a previously uncharacterized endosomal signaling pathway for a proinflammatory response in natural killer cells. (PMID:20179272)
• The expression of KIR2DL4 on NK cells in acute rejection group was statistically lower than that in stable kidney function group after renal transplantation. (PMID:21092455)
• By promoting polyubiquitylation and degradation, E3 ubiquitin ligase Triad3A is identified as an interaction partner for the KIR2DL4 cytoplasmic domain. (PMID:21270397)
• The frequencies of alleles of killer cell immunoglobulin-like receptor genes, KIR3DL3 and KIR3DL2, and the carrier frequency of KIR2DL4 alleles have been determined from a population of African Americans by DNA sequencing of the coding regions. (PMID:21607693)
• KIR2DL4 gene may not be essential for fertility, as shown in a fertile Caucasian woman missing KIR2DL4 [case report] (PMID:21623736)
• Significant differences in the frequency of KIR genes were found between the two populations despite being separated by only 300 km (PMID:22320834)
• Differential transcription factor use by the KIR2DL4 promoter under constitutive and IL-2/15-treated conditions. (PMID:22467658)
• Sustained activation through CD158d induced morphological changes in NK cell shape and size, and survival in the absence of cell-cycle entry, all hallmarks of senescence. (PMID:23184984)

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), VSTM1 (ENSG00000189068), NCR1 (ENSG00000189430), LILRB3 (ENSG00000204577), KIR2DS4 (ENSG00000221957), LILRA4 (ENSG00000239961), LILRA2 (ENSG00000239998), KIR3DL2 (ENSG00000240403), KIR3DL3 (ENSG00000242019), KIR2DL3 (ENSG00000243772), LILRA6 (ENSG00000244482), TARM1 (ENSG00000248385)

Protein

Protein identifiers

Killer cell immunoglobulin-like receptor 2DL4 — Q99706 (reviewed: Q99706)

Alternative names: CD158 antigen-like family member D, G9P, Killer cell inhibitory receptor 103AS, MHC class I NK cell receptor KIR103AS

All UniProt accessions (6): A0A0B4J1S6, A0A376A8K3, A0A376A929, A8MT18, Q99706, Q8N736

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for non-classical major histocompatibility class Ib HLA-G molecules. Recognizes HLA-G in complex with B2M/beta-2 microglobulin and a nonamer self-peptide (peptide-bound HLA-G-B2M). In decidual NK cells, binds peptide-bound HLA-G-B2M complex and triggers NK cell senescence-associated secretory phenotype as a molecular switch to promote vascular remodeling and fetal growth in early pregnancy. May play a role in balancing tolerance and antiviral-immunity at maternal-fetal interface by keeping in check the effector functions of NK, CD8+ T cells and B cells. Upon interaction with peptide-bound HLA-G-B2M, initiates signaling from the endosomal compartment leading to downstream activation of PRKDC-XRCC5 and AKT1, and ultimately triggering NF-kappa-B-dependent pro-inflammatory response.

Subunit / interactions. Interacts with peptide-bound HLA-G-B2M heterotrimeric complex. Interacts with ARRB2.

Subcellular location. Cell membrane. Early endosome membrane.

Tissue specificity. Expressed in decidual NK cells and innate lymphoid cell type I (ILC1). Expressed in a subset of peripheral NK cells.

Similarity. Belongs to the immunoglobulin superfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
Q99706-1	1	yes
Q99706-2	2, AST
Q99706-3	3, AS
Q99706-4	4, ASD1
Q99706-5	5, ASD2
Q99706-6	6

RefSeq proteins (2): NP_001074239, NP_001074241 (=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 (48 total): strand 17, sequence variant 8, splice variant 4, glycosylation site 2, disulfide bond 2, topological domain 2, sequence conflict 2, helix 2, domain 2, signal peptide 1, chain 1, mutagenesis site 1, transmembrane region 1, turn 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3WYR	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99706-F1	70.19	0.34

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): 51–97, 146–195

Glycosylation sites (2): 175, 141

Mutagenesis-validated functional residues (1):

Position	Phenotype
246–247	does not affect targeting to the endosomal compartment.

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: 126 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY, MODULE_64, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_NEGATIVE_REGULATION_OF_NATURAL_KILLER_CELL_MEDIATED_IMMUNITY, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_CELLULAR_SENESCENCE, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MODULE_75, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM

GO Biological Process (6): positive regulation of natural killer cell cytokine production (GO:0002729), immune response-regulating signaling pathway (GO:0002764), cellular defense response (GO:0006968), signal transduction (GO:0007165), negative regulation of natural killer cell mediated cytotoxicity (GO:0045953), positive regulation of cellular senescence (GO:2000774)

GO Molecular Function (3): transmembrane signaling receptor activity (GO:0004888), MHC class Ib receptor activity (GO:0032394), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), membrane (GO:0016020), early endosome membrane (GO:0031901), endosome (GO:0005768)

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
natural killer cell cytokine production	1
positive regulation of natural killer cell mediated immunity	1
positive regulation of cytokine production involved in immune response	1
regulation of natural killer cell cytokine production	1
signal transduction	1
regulation of immune response	1
defense response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
negative regulation of leukocyte mediated cytotoxicity	1
negative regulation of natural killer cell mediated immunity	1
natural killer cell mediated cytotoxicity	1
regulation of natural killer cell mediated cytotoxicity	1
positive regulation of cellular process	1
cellular senescence	1
regulation of cellular senescence	1
signaling receptor activity	1
transmembrane signaling receptor activity	1
MHC class Ib protein binding	1
immune receptor activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1
early endosome	1
endosome membrane	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

24 interactions, top by confidence:

A	B	Type	Score
TRIP6	KIR2DL4	psi-mi:“MI:0915”(physical association)	0.560
RBPMS	KIR2DL4	psi-mi:“MI:0915”(physical association)	0.560
KIR2DL4	RBPMS	psi-mi:“MI:0915”(physical association)	0.560
INCA1	KIR2DL4	psi-mi:“MI:0915”(physical association)	0.560
KIR2DL4	BPIFA1	psi-mi:“MI:0915”(physical association)	0.560
FHL5	KIR2DL4	psi-mi:“MI:0915”(physical association)	0.560
KIR2DL4	TIMMDC1	psi-mi:“MI:0915”(physical association)	0.560
FCGR3A	KIR2DL4	psi-mi:“MI:0915”(physical association)	0.400
	SCAMP3	psi-mi:“MI:0914”(association)	0.350
KIR2DL4	GPR89A	psi-mi:“MI:0914”(association)	0.350
SEMG1	LRP2	psi-mi:“MI:0914”(association)	0.350
KIR2DL4	BPIFA1	psi-mi:“MI:0915”(physical association)	0.000
KIR2DL4	INCA1	psi-mi:“MI:0915”(physical association)	0.000
KIR2DL4	FHL5	psi-mi:“MI:0915”(physical association)	0.000
TIMMDC1	KIR2DL4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (95): TRIP6 (Two-hybrid), RBPMS (Two-hybrid), KIR2DL4 (Two-hybrid), KIR2DL4 (Two-hybrid), INCA1 (Two-hybrid), BPIFA1 (Two-hybrid), HLA-G (Reconstituted Complex), HGS (Affinity Capture-MS), PNMA6A (Affinity Capture-MS), TNFRSF10B (Affinity Capture-MS), DNAJB5 (Affinity Capture-MS), PHLDB3 (Affinity Capture-MS), IPO8 (Affinity Capture-MS), TBC1D9B (Affinity Capture-MS), LDLR (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2KBC9, A1YIY0, B6A8R8, C0HJX2, C0HJX3, D3ZQX2, P08101, P0C1X9, P0DTI4, P12314, P12318, P26151, P43626, P43627, P43628, P43629, P43630, P43631, P43632, P83555, P83556, P97484, Q01965, Q13291, Q14943, Q14952, Q14953, Q14954, Q28942, Q3B8P2, Q60513, Q61450, Q63203, Q64281, Q68SN8, Q6UX27, Q7TQA1, Q7Z6M3, Q8BG84, Q8BHK6

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

1 interactions.

A	Effect	B	Mechanism
HLA-G	up-regulates	KIR2DL4	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	25
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1078 predictions. Top by Δscore:

Variant	Effect	Δscore
19:54806240:CACAG:C	donor_loss	0.9900
19:54806241:ACAGG:A	donor_loss	0.9900
19:54806242:CAGG:C	donor_loss	0.9900
19:54806243:AGG:A	donor_loss	0.9900
19:54806244:GGTGA:G	donor_loss	0.9900
19:54806245:G:GC	donor_loss	0.9900
19:54806246:T:G	donor_loss	0.9900
19:54813738:GGGAG:G	donor_gain	0.9900
19:54813739:GGAGG:G	donor_gain	0.9900
19:54804994:GGACC:G	donor_gain	0.9800
19:54804995:G:T	donor_gain	0.9800
19:54805947:CCA:C	acceptor_loss	0.9800
19:54805948:CAGG:C	acceptor_loss	0.9800
19:54805949:AGGTC:A	acceptor_loss	0.9800
19:54805950:GGTCT:G	acceptor_gain	0.9800
19:54806251:A:T	donor_gain	0.9800
19:54813740:G:T	donor_gain	0.9800
19:54804909:A:T	donor_gain	0.9700
19:54804953:G:GT	donor_gain	0.9700
19:54813229:G:GG	donor_gain	0.9700
19:54805065:A:AG	donor_gain	0.9600
19:54805949:A:AG	acceptor_gain	0.9600
19:54805950:G:GG	acceptor_gain	0.9600
19:54812482:G:GT	donor_gain	0.9600
19:54803923:GTGG:G	donor_gain	0.9500
19:54804954:A:T	donor_gain	0.9500
19:54806209:C:A	donor_gain	0.9500
19:54813836:CTCCA:C	acceptor_loss	0.9500
19:54813837:TCCAG:T	acceptor_loss	0.9500
19:54813838:CCAG:C	acceptor_loss	0.9500

AlphaMissense

2236 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000922558 (19:54804428 C>A,G,T), RS1001230224 (19:54806171 A>G), RS1001396045 (19:54804212 G>A), RS1002952738 (19:54802314 C>G,T), RS1002982255 (19:54802015 G>A,T), RS1003508705 (19:54814746 G>A,C), RS1003830617 (19:54805444 G>A,C), RS1004163265 (19:54805651 T>A,C,G), RS1004885303 (19:54805969 C>T), RS1005826156 (19:54807005 C>T), RS1005900345 (19:54806801 G>A), RS1006100493 (19:54802614 T>A), RS1006184257 (19:54803744 G>A,T), RS1006360125 (19:54809579 A>C,G), RS1006887844 (19:54803995 G>A)

Disease associations

OMIM: gene MIM:604945 | 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
GCST003159_3	Objective response to lithium treatment	1.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
GSK-J4	decreases expression	1
quercitrin	affects expression	1
butyraldehyde	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Arsenic	affects expression	1
Azacitidine	increases secretion, affects binding, increases reaction, decreases methylation, increases expression	1
Benzo(a)pyrene	affects methylation	1
Methylcholanthrene	affects binding, increases reaction	1
Polychlorinated Biphenyls	affects expression	1
Silicon Dioxide	decreases expression	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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