KIR2DL1

Summary

KIR2DL1 (killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1, HGNC:6329) is a protein-coding gene on chromosome 19q13.42, encoding Killer cell immunoglobulin-like receptor 2DL1 (P43626). Receptor on natural killer (NK) cells for some HLA-C alleles such as w4 and w6.

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 3802 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 18 total
• Phenotypes (HPO): 1
• Druggable target: yes
• MANE Select transcript: NM_014218

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6329
Approved symbol	KIR2DL1
Name	killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1
Location	19q13.42
Locus type	gene with protein product
Status	Approved
Aliases	cl-42, nkat1, 47.11, p58.1, CD158A
Ensembl gene	ENSG00000125498
Ensembl biotype	protein_coding
OMIM	604936
Entrez	3802

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000291633, ENST00000336077, ENST00000885740

RefSeq mRNA: 1 — MANE Select: NM_014218 NM_014218

CCDS: CCDS12904

Canonical transcript exons

ENST00000336077 — 8 exons

Exon	Start	End
ENSE00001900463	54783637	54784322
ENSE00001920028	54769793	54769884
ENSE00002516631	54778612	54778662
ENSE00002519960	54773333	54773632
ENSE00002534224	54775165	54775458
ENSE00003472195	54782922	54783023
ENSE00003553013	54783486	54783538
ENSE00003649082	54770849	54770884

Expression profiles

Bgee: expression breadth broad, 31 present calls, max score 85.51.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2082 / max 104.2041, expressed in 34 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177550	0.1365	33
177549	0.0717	20

Top tissues by expression

97 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	85.51	silver quality
granulocyte	CL:0000094	77.88	gold quality
blood	UBERON:0000178	70.86	gold quality
spleen	UBERON:0002106	58.08	gold quality
right lung	UBERON:0002167	56.93	gold quality
upper lobe of left lung	UBERON:0008952	51.40	gold quality
bone marrow	UBERON:0002371	49.50	gold quality
leukocyte	CL:0000738	48.48	gold quality
bone marrow cell	CL:0002092	48.36	gold quality
lung	UBERON:0002048	48.36	gold quality
endometrium	UBERON:0001295	46.58	gold quality
monocyte	CL:0000576	45.94	gold quality
placenta	UBERON:0001987	45.90	gold quality
right lobe of liver	UBERON:0001114	43.96	silver quality
colonic epithelium	UBERON:0000397	41.25	gold quality
stromal cell of endometrium	CL:0002255	41.11	silver quality
apex of heart	UBERON:0002098	40.97	silver quality
omental fat pad	UBERON:0010414	37.08	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
adipose tissue	UBERON:0001013	36.24	gold quality
sural nerve	UBERON:0015488	35.90	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
subcutaneous adipose tissue	UBERON:0002190	35.46	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	35.38	gold quality
right coronary artery	UBERON:0001625	35.37	gold quality
thoracic mammary gland	UBERON:0005200	33.96	silver quality
smooth muscle tissue	UBERON:0001135	33.61	gold quality
duodenum	UBERON:0002114	32.72	gold quality
mucosa of stomach	UBERON:0001199	32.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.54

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

22 targeting KIR2DL1, 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-1277-5P	100.00	73.95	5056
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-567	99.63	68.57	1219
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-5697	99.39	67.74	1249
HSA-MIR-133A-5P	99.28	69.13	941
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-1301-3P	98.64	68.27	1071
HSA-MIR-5047	98.64	68.62	1035
HSA-MIR-7156-3P	98.25	67.66	859
HSA-MIR-18B-3P	98.05	65.55	595
HSA-MIR-3144-5P	97.64	65.45	646
HSA-MIR-4670-3P	97.37	68.35	1378
HSA-MIR-643	97.35	67.91	805
HSA-MIR-134-3P	96.83	66.22	1001

Literature-anchored findings (GeneRIF, showing 40)

• interrupts TCR signaling, preventing dynamic membrane reorganization in CTL/tumor cell interaction (PMID:12351398)
• The engagement of the activating isoforms of killer Ig-like receptor (KIR)(CD158a or CD158b) by their natural ligands, represented by soluble HLA-I molecules, induced programmed cell death of natural killer cells (PMID:12393468)
• Positive linkage disequilibrium was seen between KRI2DL1 and KIR2DL3. (PMID:12559621)
• The unique property of KIR2DL1 to become phosphorylated in the absence of adhesion and actin cytoskeleton rearrangement explains how KIRs can efficiently block early activation signals during NK-target cell contacts. (PMID:12794140)
• Increased binding to influenza virus-infected cells is observed in the killer cell Ig-like receptor 2 domain long tail 1, binding that is functional and possibly results from generation of complexes of class I MHC proteins after influenza virus infection. (PMID:12847262)
• A significant decrease in NK cell CD158a expression was demonstrated in recurrent spontaneous abortion women (PMID:15209394)
• KIR2DS1 and KIR2DL1 share sensitivity to peptide sequence alterations. These results fit a model in which activating and inhibitory receptors recognize the same sets of self-MHC class I molecules, differing only in their binding affinities. (PMID:16141329)
• Posttranslational modifications such as phosphorylation of a presented KIR2DL peptide alters the ability of natural killer (NK) cells to recognize MHC class I molecule HLA-Cw4, and results in improved NK cell killing. (PMID:16709835)
• This is a new killer immunoglobulin-like receptor allele. (PMID:16774543)
• alleles 2DL1*00302 and *002 were frequently observed in addition to two other known alleles and four new alleles, 2DL1*00402, 2DL1*007, 2DL1*008, and 2DL1*009 in three families and 77 bone marrow transplant patients and donors (PMID:17493149)
• Data show that there was no correlation between CD15ab expression and disease activity in rheumatoid arthritis. (PMID:17497034)
• CD158a and CD158b display a coactivatory function, involving the c-Jun NH2-terminal protein kinase signaling pathway, when expressed on malignant CD4+ T cells from a patient with Sezary syndrome (PMID:17522341)
• KIR2DL1 may induce 2 opposite signaling outputs in CD4(+) T cells, depending on whether the KIR receptor is bound to its ligand. (PMID:18574028)
• The role of this investigation has been to create a base of genetic information in relation to both KIR2DL1 and KIR2DS1 allele diversity. (PMID:18643963)
• study suggests that the activating KIR2DS4 may serve as CML susceptive gene to trigger leukemia development, while KIR2DS3 is possibly a protect gene of ALL (PMID:19450876)
• DNA-demethylating treatment with 5-azacytidine resulted in re-expression of kir2DL1 gene and increased expressions of kir2DL1, kir2DL2 and kir2DL3 genes in NK-92MI cells. (PMID:19549382)
• Contrary to CD158a and CD158b killer immunoglobulin-like receptors (KIRs), there is a significant positive correlation of NKG2D and CD161 expression with NK cytotoxicity. (PMID:19711124)
• Findings provide novel insights into the molecular determinant of KIR2DL1 and conceivably a fundamental understanding of KIR2DL1 allelic polymorphism in human disease susceptibility, transplant outcome, and donor selection. (PMID:19828694)
• Data show that KIR activation and HLA expression density are critical determinants for the efficacy of rituximab treatment. (PMID:20056126)
• Eleven new KIR2DL1 alleles were identified by DNA sequencing of the coding region from amplified genomic DNA from 100 random African Americans (PMID:20210923)
• The KIR2DL1 gene polymorphism and KIR/HLA-C gene compatibility are associated with type 1 diabetes. (PMID:20356536)
• Results suggest a protective role of KIR2DL1/C2 in T1D. (PMID:20580654)
• Inhibitory receptor KIR2DL1 in combination with HLA-C2 ligand confers susceptibility to chronic hepatitis B (CHB), whereas inhibitory receptor KIR2DL3 or KIR2DL3 homozygote in the presence of HLA-C1C1 genotype shows protection against CHB. (PMID:20643584)
• supervillin is a novel molecule that associates with KIR2DL1 receptor and regulates the inhibitory signaling in NK cells. (PMID:21070852)
• Results demonstrate that receptor-ligand dimensions, NKG2D/MICA and KIR2DL1/HLA-C, are important in NK cell recognition. (PMID:21179506)
• cytomegalovirus positive had lower proportions of NK-cells expressing inhibitory receptors (KLRG1 and CD158a) (PMID:21933704)
• 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)
• NK cells were isolated from peripheral blood and the lysis of KG1A and K562 cells by the NK cells was analyzed to investigate whether KIR2DL1 expression on NK cells would affect the cytotoxicity. (PMID:23865361)
• Normal NK CD158a expression is associated with successful IVF and pregnancy. (PMID:23951916)
• Array CGH showed a 95 Kb de novo duplication on chromosome 19q13.4 encompassing four killer cell immunoglobulin-like receptor (KIR) genes. (PMID:23952617)
• Donor KIR2DL1 allelic polymorphism affects recipient outcomes after allogeneic hematopoietic stemm cell transplantation. (PMID:24043749)
• Our findings suggest KIR2DL1(+)-HLA-C2(+) genotype as heritable risk factor in oral squamous cell carcinoma (OSCC) predisposing to OSCC at a younger age. (PMID:24818561)
• genetic association studies in Chinese Han population: Data suggest that the frequency of KIR2DL1 gene is increased in women with pre-eclampsia when homozygous HLA-C2 allele appears in the fetus. (PMID:24951171)
• We investigated the association of HLA alleles and KIR ligands according to oligoclonal band status in multiple sclerosis patients. (PMID:25037176)
• C2 of KIR2DL1 is a novel risk factor, and homozygosity for C1 is a protective factor for childhood B-ALL (PMID:25163702)
• These results revealed that ITIM phosphorylation is controlled by self-association of KIR and that His-36 serves as a gatekeeper to prevent unregulated signaling through KIR2DL1. (PMID:25505289)
• KIR2DL1*022 and 2DL1*026 evolved in the KhoeSan after their divergence from other modern human populations. (PMID:26292085)
• Data suggest regulatory interactions between major histocompatibility antigen HLA-C and killer cell Ig-like receptor (KIR) might promote Graft-versus-Leukemia effects following transplantation. (PMID:26416275)
• Coengagement of inhibitory receptors, either KIR2DL1 or CD94-NKG2A, did not inhibit phosphorylation of Stat5 but inhibited selectively phosphorylation of Akt and S6 ribosomal protein. (PMID:26453750)
• Influence of Differently Licensed KIR2DL1-Positive Natural Killer Cells in Transplant Recipients with Acute Leukemia (PMID:26456260)

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), LILRB2 (ENSG00000131042), IGSF1 (ENSG00000147255), LAIR2 (ENSG00000167618), KIR3DL1 (ENSG00000167633), OSCAR (ENSG00000170909), FCAR (ENSG00000186431), LILRB4 (ENSG00000186818), LILRA5 (ENSG00000187116), KIR2DL4 (ENSG00000189013), 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 2DL1 — P43626 (reviewed: P43626)

Alternative names: CD158 antigen-like family member A, Natural killer-associated transcript 1, p58 natural killer cell receptor clones CL-42/47.11, p58.1 MHC class-I-specific NK receptor

All UniProt accessions (1): P43626

UniProt curated annotations — full annotation on UniProt →

Function. Receptor on natural killer (NK) cells for some HLA-C alleles such as w4 and w6. Inhibits the activity of NK cells thus preventing cell lysis.

Subunit / interactions. Interacts with ARRB2. Interacts with PTPN6; the interaction is enhanced by ARRB2. Interacts with PTPN11; the interaction is enhanced by ARRB2.

Subcellular location. Cell membrane.

Tissue specificity. Expressed by NK cells.

Similarity. Belongs to the immunoglobulin superfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P43626-1	1	yes
P43626-2	2

RefSeq proteins (1): NP_055033* (*=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 19, sequence variant 11, glycosylation site 4, disulfide bond 2, topological domain 2, mutagenesis site 2, domain 2, signal peptide 1, chain 1, splice variant 1, transmembrane region 1, helix 1, region of interest 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1NKR	X-RAY DIFFRACTION	1.7
9HML	X-RAY DIFFRACTION	2.17
1IM9	X-RAY DIFFRACTION	2.8
9F2D	X-RAY DIFFRACTION	2.89

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43626-F1	75.36	0.51

Antibody-complex structures (SAbDab): 1 — 9HML

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 (4): 144, 178, 67, 84

Mutagenesis-validated functional residues (2):

Position	Phenotype
302	abolishes interaction with arrb2; when associated with a-332. diminishes interaction with arrb2.
332	abolishes interaction with arrb2; when associated with a-302.

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: 43 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_IMMUNE_RESPONSE, KEGG_GRAFT_VERSUS_HOST_DISEASE, GNF2_IL2RB, KEGG_ANTIGEN_PROCESSING_AND_PRESENTATION, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, ZHOU_INFLAMMATORY_RESPONSE_LIVE_UP, GOBP_IMMUNE_RESPONSE_REGULATING_SIGNALING_PATHWAY, GOBP_IMMUNE_RESPONSE_INHIBITING_SIGNAL_TRANSDUCTION, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, KRAS.DF.V1_DN, GOMF_IMMUNE_RECEPTOR_ACTIVITY, MIR297, MIR4670_3P, MIR5697

GO Biological Process (3): immune response-regulating signaling pathway (GO:0002764), natural killer cell inhibitory signaling pathway (GO:0002769), immune response (GO:0006955)

GO Molecular Function (2): signaling receptor activity (GO:0038023), 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
signal transduction	1
regulation of immune response	1
immune response-inhibiting cell surface receptor signaling pathway	1
immune system process	1
response to stimulus	1
molecular transducer activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

792 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KIR2DL1	HLA-C	P04222	999
KIR2DL1	HLA-A	P01891	957
KIR2DL1	HLA-B	P01889	946
KIR2DL1	KLRD1	Q13241	936
KIR2DL1	HLA-E	P13747	911
KIR2DL1	KLRC1	P26715	905
KIR2DL1	SORBS1	Q9BX66	874
KIR2DL1	KLRC2	P26717	868
KIR2DL1	TRIM45	Q9H8W5	851
KIR2DL1	STAC	Q99469	816
KIR2DL1	TYROBP	O43914	788
KIR2DL1	KIR2DL4	P78400	787
KIR2DL1	KLRK1	P26718	772
KIR2DL1	NCR3	O14931	771
KIR2DL1	SPART	Q8N0X7	763

IntAct

40 interactions, top by confidence:

A	B	Type	Score
KIR2DL1	HLA-C	psi-mi:“MI:0407”(direct interaction)	0.790
KIR2DL1	HLA-C	psi-mi:“MI:0915”(physical association)	0.790
PIK3R1	KIR2DL1	psi-mi:“MI:0915”(physical association)	0.490
PTPN11	KIR2DL1	psi-mi:“MI:0915”(physical association)	0.490
PTPN6	KIR2DL1	psi-mi:“MI:0914”(association)	0.460
KIR2DL1	HLA-C	psi-mi:“MI:0407”(direct interaction)	0.440
KIR2DL1	HLA-Cw	psi-mi:“MI:0407”(direct interaction)	0.440
HLA-C	KIR2DL1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (31): HLA-C (Reconstituted Complex), KIR2DL1 (Reconstituted Complex), HLA-C (Reconstituted Complex), KIR2DL1 (Reconstituted Complex), HLA-C (Co-crystal Structure), GOSR1 (Affinity Capture-MS), PTPRD (Affinity Capture-MS), KIR2DL2 (Affinity Capture-MS), KIR2DS3 (Affinity Capture-MS), SLC4A7 (Affinity Capture-MS), FAM114A2 (Affinity Capture-MS), LSR (Affinity Capture-MS), KIR3DL1 (Affinity Capture-MS), STX10 (Affinity Capture-MS), ST3GAL3 (Affinity Capture-MS)

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, C0HJX2, C0HJX3, D3ZQX2, O75019, O75022, O75023, O76036, P0C191, P24071, P43626, P43629, P43630, P59901, P83556, P97484, Q14943, Q14954, Q61450, Q64281, Q6GTX8, Q6ISS4, Q6PI73, Q7TQA1, Q863H2, Q8C567, Q8IYS5, Q8MJZ2, Q8MJZ7, Q8N109, Q8N149, Q8N423, Q8N6C8, Q8N743, Q8NHJ6, Q8NHK3, Q8NHL6, Q95JB9, Q9HCN6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	2
Likely benign	14
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1212 predictions. Top by Δscore:

Variant	Effect	Δscore
19:54782916:TTCCA:T	acceptor_loss	1.0000
19:54782917:TCCA:T	acceptor_loss	1.0000
19:54782918:CCAG:C	acceptor_loss	1.0000
19:54782919:CAGG:C	acceptor_loss	1.0000
19:54782920:A:AG	acceptor_gain	1.0000
19:54782920:AG:A	acceptor_gain	1.0000
19:54782921:G:GA	acceptor_gain	1.0000
19:54782921:GG:G	acceptor_gain	1.0000
19:54782921:GGT:G	acceptor_gain	1.0000
19:54782921:GGTA:G	acceptor_gain	1.0000
19:54782921:GGTAA:G	acceptor_gain	1.0000
19:54783019:AAAAA:A	donor_gain	1.0000
19:54783020:AAAA:A	donor_gain	1.0000
19:54783020:AAAAG:A	donor_loss	1.0000
19:54783021:AAA:A	donor_gain	1.0000
19:54783022:AA:A	donor_gain	1.0000
19:54783023:AG:A	donor_loss	1.0000
19:54783024:G:GG	donor_gain	1.0000
19:54783024:GTAA:G	donor_loss	1.0000
19:54783025:T:A	donor_loss	1.0000
19:54783411:ATGTT:A	acceptor_gain	1.0000
19:54783412:T:G	acceptor_gain	1.0000
19:54783538:GGTA:G	donor_loss	1.0000
19:54783539:G:A	donor_loss	1.0000
19:54783539:G:GG	donor_gain	1.0000
19:54783540:T:G	donor_loss	1.0000
19:54769881:GTTG:G	donor_gain	0.9900
19:54769885:G:GG	donor_gain	0.9900
19:54769886:TGAG:T	donor_loss	0.9900
19:54773332:GGA:G	acceptor_gain	0.9900

AlphaMissense

2263 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:54773605:A:C	S115R	0.943
19:54773607:T:A	S115R	0.943
19:54773607:T:G	S115R	0.943
19:54775347:T:C	F185L	0.919
19:54775349:T:A	F185L	0.919
19:54775349:T:G	F185L	0.919
19:54773434:T:C	F58L	0.915
19:54773436:C:A	F58L	0.915
19:54773436:C:G	F58L	0.915
19:54775431:A:C	S213R	0.906
19:54775433:T:A	S213R	0.906
19:54775433:T:G	S213R	0.906
19:54775239:T:A	C149S	0.893
19:54775240:G:C	C149S	0.893
19:54769869:A:C	S7R	0.885
19:54769871:C:A	S7R	0.885
19:54769871:C:G	S7R	0.885
19:54773560:T:A	C100S	0.884
19:54773561:G:C	C100S	0.884
19:54775389:T:C	F199L	0.880
19:54775391:C:A	F199L	0.880
19:54775391:C:G	F199L	0.880
19:54773515:T:C	F85L	0.878
19:54773517:C:A	F85L	0.878
19:54773517:C:G	F85L	0.878
19:54773425:T:C	F55L	0.871
19:54773427:T:A	F55L	0.871
19:54773427:T:G	F55L	0.871
19:54775386:T:A	C198S	0.870
19:54775387:G:C	C198S	0.870

dbSNP variants (sampled 300 via entrez): RS1000058870 (19:54851068 G>A,C), RS1000067648 (19:54774776 T>A,G), RS1000072506 (19:54862515 G>A), RS1000366378 (19:54851755 G>A), RS1000513175 (19:54859458 G>C), RS1000973765 (19:54847209 G>A,T), RS1000990420 (19:54772772 C>G,T), RS1001031830 (19:54866105 T>A), RS1001062397 (19:54772143 G>A,C,T), RS1001130887 (19:54863414 C>A,T), RS1001142856 (19:54860257 G>C,T), RS1001149346 (19:54782731 T>G), RS1001479341 (19:54847003 G>A,T), RS1001581690 (19:54768643 G>A), RS1001638929 (19:54854233 C>G)

Disease associations

OMIM: gene MIM:604936 | disease phenotypes: MIM:148300

GenCC curated gene-disease

Mondo (2): breast ductal adenocarcinoma (MONDO:0005590), keratoconus (MONDO:0015486)

Orphanet (2): OBSOLETE: Keratoconus (Orphanet:156071), NON RARE IN EUROPE: Isolated keratoconus (Orphanet:2335)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000563	Keratoconus

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001725_62	Inflammatory bowel disease	7.000000e-11

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D007640	Keratoconus	C11.204.627

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712912 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Azacitidine	decreases methylation, increases expression	2
Zoledronic Acid	increases expression	1
Arsenic	affects expression	1
Benzo(a)pyrene	affects methylation	1
Smoke	increases expression	1
Valproic Acid	increases methylation	1

Cellosaurus cell lines

3 cell lines: 2 induced pluripotent stem cell, 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4YU	SUi003-A	Induced pluripotent stem cell	Male
CVCL_A4YV	SUi003-B	Induced pluripotent stem cell	Male
CVCL_E5II	CHO-K1/KIR	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01485211	PHASE4	COMPLETED	Corneal Thickness Changes During Corneal Collagen Cross-linking With Ultraviolet-A Irradiation and Riboflavin
NCT02119039	PHASE4	COMPLETED	Effect of CACICOL20 on Corneal Epithelial Healing After Cross-linking in Patients With Keratoconus
NCT03245853	PHASE4	COMPLETED	Epi-On Corneal Crosslinking for Keratoconus
NCT03429569	PHASE4	UNKNOWN	Cross-Linking ACcéléré Iontophorèse Confocal kératocONE
NCT04427956	PHASE4	COMPLETED	Corneal Crosslinking Treatment Study
NCT07474870	PHASE4	NOT_YET_RECRUITING	Outcomes of CTAK Surgery
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00371202	PHASE3	UNKNOWN	Comparison of Penetrating Keratoplasty and Deep Lamellar Keratoplasty With the Big Bubble Technique for Keratoconus
NCT00647699	PHASE3	COMPLETED	Corneal Collagen Cross-linking for Progressive Keratoconus
NCT00815256	PHASE3	UNKNOWN	Safety and Effectiveness of Collagen Cross Linking in Progressive Mild and Moderate Keratoconus
NCT00887900	PHASE3	COMPLETED	Deep Anterior Lamellar Keratoplasty (DALK)
NCT01112072	PHASE3	UNKNOWN	Corneal Collagen Crosslinking and Intacs for Keratoconus and Ectasia
NCT01152541	PHASE3	UNKNOWN	Corneal Collagen Crosslinking for Progressive Keratoconus and Ectasia Using Riboflavin/Dextran and Hypotonic Riboflavin
NCT01190306	PHASE3	TERMINATED	Safety Study of the VEGA UV-A System to Treat Keratoconus
NCT01344187	PHASE3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01459679	PHASE3	TERMINATED	Safety & Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus or Corneal Ectasia After Refractive Surgery
NCT01464268	PHASE3	UNKNOWN	Transepithelial Corneal Collagen Crosslinking for Keratoconus and Corneal Ectasia
NCT01604135	PHASE3	ACTIVE_NOT_RECRUITING	Collagen Crosslinking for Keratoconus - a Randomized Controlled Clinical Trial
NCT01643226	PHASE3	COMPLETED	Safety and Efficacy Study of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT01672814	PHASE3	COMPLETED	Microwave Treatment and Corneal Collagen Crosslinking for Keratoconus
NCT01682993	PHASE3	TERMINATED	Corneal Cross Linking and Topography Guided Excimer Laser Treatment
NCT01972854	PHASE3	TERMINATED	Safety and Efficacy of Corneal Collagen Cross-Linking in Eyes With Keratoconus
NCT02613780	PHASE3	UNKNOWN	Refractive Treatment of Early Keratoconus
NCT02638376	PHASE3	UNKNOWN	Evaluating the Safety and Efficacy of the KXL System for Corneal Collagen Cross-Linking in Eyes Having Keratoconus
NCT03080077	PHASE3	UNKNOWN	Safety and Effectiveness of Corneal Crosslinking (CXL): Keratoconus and Post-Refractive Ectasia
NCT03187912	PHASE3	COMPLETED	Accelerated Corneal Cross-linking With Different Riboflavin Solutions
NCT03442751	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Epi-on Corneal Cross-linking in Eyes With Progressive Keratoconus
NCT03858036	PHASE3	UNKNOWN	Corneal Collagen Cross-Linking (CXL) Performed With Epi-ON Versus Epi-OFF in Eyes With Keratoconus and Other Corneal Ectatic Disorders
NCT04897503	PHASE3	UNKNOWN	Corneal Collagen Crosslinking for Keratoconus and Ectasia Using Riboflavin/Dextran or Riboflavin/Methylcellulose
NCT04905108	PHASE3	UNKNOWN	Transepithelial (Epi-on) Corneal Collagen Crosslinking to Treat Keratoconus and Corneal Ectasia
NCT05027295	PHASE3	UNKNOWN	Accelerated Corneal Collagen Crosslinking for Keratoconus and Ectasia Using Pulse or Continuous UV-A Light
NCT06100939	PHASE3	ACTIVE_NOT_RECRUITING	Epithelium-On Corneal Cross-linking in Subjects 8 to 45 Years of Age With Keratoconus
NCT06100952	PHASE3	ACTIVE_NOT_RECRUITING	Epithelium-On Corneal Cross-linking in Subjects 8 to 45 Years of Age with Keratoconus
NCT06450470	PHASE3	RECRUITING	Use of a Freeze-dried Amniotic Membrane Post Crosslinking in Subjects With Progressive Keratoconus
NCT06601101	PHASE3	RECRUITING	Effects of Topical Insulin on Corneal Epithelium Healing After Corneal Crosslinking in Patients With Keratoconus
NCT07124910	PHASE3	RECRUITING	Comparison of Epi-ON Corneal Collagen Crosslinking Performed Using an 18-Minute UVA Exposure vs. a 24-Minute UVA Exposure on Eyes With Ectatic Corneal Diseases
NCT07135167	PHASE3	RECRUITING	Compassionate Use Study of Epi-ON Corneal Collagen Crosslinking Performed Using UVA Exposure on Eyes With Ectatic Corneal Diseases for Subjects With Down Syndrome
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00409955	PHASE2	COMPLETED	Lamellar Transplant With Lyophilized Corneas