ANKK1

Summary

ANKK1 (ankyrin repeat and kinase domain containing 1, HGNC:21027) is a protein-coding gene on chromosome 11q23.2, encoding Ankyrin repeat and protein kinase domain-containing protein 1 (Q8NFD2).

The protein encoded by this gene belongs to the Ser/Thr protein kinase family, and protein kinase superfamily involved in signal transduction pathways. This gene is closely linked to DRD2 gene (GeneID:1813) on chr 11, and a well studied restriction fragment length polymorphism (RFLP) designated TaqIA, was originally associated with the DRD2 gene, however, later was determined to be located in exon 8 of ANKK1 gene (PMIDs: 18621654, 15146457), where it causes a nonconservative amino acid substitution. It is not clear if this gene plays any role in neuropsychiatric disorders previously associated with Taq1A RFLP.

Source: NCBI Gene 255239 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 162 total
• Phenotypes (HPO): 1
• Druggable target: yes — 17 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_178510

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21027
Approved symbol	ANKK1
Name	ankyrin repeat and kinase domain containing 1
Location	11q23.2
Locus type	gene with protein product
Status	Approved
Aliases	X-kinase
Ensembl gene	ENSG00000170209
Ensembl biotype	protein_coding
OMIM	608774
Entrez	255239

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 nonsense_mediated_decay

ENST00000303941, ENST00000542948

RefSeq mRNA: 1 — MANE Select: NM_178510 NM_178510

CCDS: CCDS44734

Canonical transcript exons

ENST00000303941 — 8 exons

Exon	Start	End
ENSE00001130275	113398964	113400416
ENSE00001210756	113396067	113396222
ENSE00001210762	113393481	113393775
ENSE00001210771	113387779	113388069
ENSE00001247337	113397980	113398016
ENSE00001247345	113397224	113397342
ENSE00003462254	113395359	113395408
ENSE00003686979	113394929	113395080

Expression profiles

Bgee: expression breadth ubiquitous, 121 present calls, max score 80.21.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0414 / max 11.8820, expressed in 18 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116759	0.0414	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	80.21	gold quality
pituitary gland	UBERON:0000007	70.95	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	69.81	gold quality
adenohypophysis	UBERON:0002196	69.22	gold quality
skin of leg	UBERON:0001511	68.04	gold quality
zone of skin	UBERON:0000014	67.70	gold quality
skin of abdomen	UBERON:0001416	67.17	gold quality
granulocyte	CL:0000094	65.44	gold quality
fallopian tube	UBERON:0003889	65.05	gold quality
left uterine tube	UBERON:0001303	64.81	gold quality
endocervix	UBERON:0000458	62.01	gold quality
minor salivary gland	UBERON:0001830	61.71	gold quality
nucleus accumbens	UBERON:0001882	61.41	gold quality
right adrenal gland cortex	UBERON:0035827	61.41	gold quality
saliva-secreting gland	UBERON:0001044	61.38	gold quality
prostate gland	UBERON:0002367	61.09	gold quality
vagina	UBERON:0000996	60.82	gold quality
right adrenal gland	UBERON:0001233	60.66	gold quality
uterine cervix	UBERON:0000002	59.23	gold quality
spleen	UBERON:0002106	58.98	gold quality
bone marrow cell	CL:0002092	58.58	gold quality
ectocervix	UBERON:0012249	58.10	gold quality
right ovary	UBERON:0002118	57.11	gold quality
left adrenal gland cortex	UBERON:0035825	57.04	gold quality
putamen	UBERON:0001874	56.93	gold quality
hypothalamus	UBERON:0001898	56.92	gold quality
left ovary	UBERON:0002119	56.92	gold quality
thoracic mammary gland	UBERON:0005200	56.46	gold quality
left adrenal gland	UBERON:0001234	56.45	gold quality
ovary	UBERON:0000992	55.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.53

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

5 targeting ANKK1, 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-4776-3P	100.00	68.73	1340
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-374B-3P	98.63	68.24	1360
HSA-MIR-4659B-5P	98.03	66.84	979
HSA-MIR-4659A-5P	98.03	66.42	819

Literature-anchored findings (GeneRIF, showing 40)

• Among the aged with cognitive impairments, the homozygous status for the A2 allele of the DRD2 Taq I polymorphism is associated with diminished cognitive performance and increased atrophy in the striatum. (PMID:12151753)
• study suggests that only the TaqI A polymorphism is associated with neuroleptic malignant syndrome, but the -141 C Ins/Del and Ser(9)Gly polymorphisms are not (PMID:12555236)
• There is a lack of association in Japanese patients between neuroleptic malignant syndrome and the TaqI A polymorphism of this gene. (PMID:12605103)
• a possible linkage with schizophrenia for the Taq1A marker but not for the Taq1B marker of DRD2 gene. (PMID:12762588)
• changes in ANKK1 activity may provide an alternative explanation for previously described associations between the DRD2 Taq1A RFLP and neuropsychiatric disorders such as addiction (PMID:15146457)
• It is suggested that in methamphetamine psychosis the TaqI A polymorphism of dopamine D2 receptor not only regulates prolongation of psychosis symptoms but also influences the form of the temporal lobe. (PMID:15542731)
• the TaqIA1 allele of the dopamine receptor gene D2 has been associated with alcoholism, as well as with other addictive behaviours (PMID:15545020)
• for men, but not for women, we observed a strong and specific association between low neuroticism-anxiety and the A1+ allele of the DRD2 TaqI A polymorphism (PMID:15812318)
• APM linkage analysis suggested that the DD2R gene TaqI polymorphism had evidence of linkage with blood pressure, as well as with obesity. (PMID:15939106)
• This study investigated two dopaminergic candidate genes (COMT VAL158MET and DRD2 TAQ IA) for endophenotypes of cognitive functioning. Results showed an interaction effect of DRD2xVAL on interference performance as measured by the STROOP-test. (PMID:16026865)
• alcoholic and non-alcoholic smokers presented a higher frequency of the DRD2 TaqI A1 allele (P = 0.04) than non-smoking controls (PMID:16032443)
• Utilize the attention network test and find that carriers of the A1 allele show gene-associated functional activation in an anatomically specific, dopamine-rich region of the brain comprising the anterior cingulate gyrus. (PMID:16869231)
• No support for an association between early onset alcohol use disorders and the DRD2 TaqIA polymorphism. (PMID:17069991)
• A DRD2 polymorphic TaqIA restriction endonuclease site is associated with increase risk of violence or serious delinquency in male adolescents and young adults (ages 12 to 23). (PMID:17120049)
• Smokers homozygous for the DRD2 TaqI-B2 allele experience progressive improvement in self-reported withdrawal symptoms while smokers with the TaqI-B1 allele show little change. (PMID:17189962)
• study supports other family-based association tests that have reported no association between the DRD2 TaqIA polymorphism and alcohol abuse and dependence (PMID:17446975)
• Results of this meta-analysis support the association of the DRD2 Taq1A polymorphism with alcoholism. (PMID:17453061)
• In our study DRD2 C939T was in strong linkage disequilibrium with TaqIA in tardive dyskinesia in schizophrenia. (PMID:17669630)
• Polymorphisms TaqI A of the DRD2 is associated with childhood attention deficit hyperactivity disorder (PMID:17671965)
• association studies of alcohol dependence and 43 SNPs mapped to the gene cluster of NCAM1, TTC12, ANKK1 and DRD2 (PMID:17761687)
• The Taq1A of D2 dopamine receptor is associated with tardive dyskinesia . (PMID:17767146)
• More extensive genotyping across DRD2 and ANKK1 suggests that the association with alcohol dependence observed in this region may be due to genetic variants in the ANKK1 gene. (PMID:17850642)
• Findings do not support the hypothesis that two of the most prominent dopaminergic candidate loci (DRD2 Taq Ia and COMT Val158Met) effect prepulse inhibition the study does not exclude the relevance of the dopaminergic system in general. (PMID:18037170)
• These data suggest that bupropion may be effective for smoking cessation only in a subgroup of smokers with the DRD2 Taq1 A2/A2 genotype. (PMID:18058343)
• These findings suggest a modest association between DRD2 genotype and quitting behavior in male cigarette smokers in Egypt. (PMID:18058350)
• A significant association was found between the dopamine D2 receptor gene TaqI A genotype and “Eros” (a loving style characterized by a tendency to develop intense emotional experiences based on the physical attraction to the partner). (PMID:18063936)
• Taq1A polymorphism in DRD2 gene significantly influenced the time course of prolactin response to perphenazine (PMID:18075468)
• This study finding significant associations between the A1 allele of the DRD2 TaqI A polymorphism and reward-related personality traits. (PMID:18259088)
• study found a significant linkage with cigarette consumption and ANKK1 in African Americans, identified a possible causative single nucleotide polymorphism, and showed that the variant alters expression level of NF-kappaB-regulated genes (PMID:18354387)
• The TaqI-A of the ANKK1 gene and the C957T of the DRD2 gene are epistatically associated with psychopathic traits in alcohol-dependent patients. (PMID:18669994)
• We explored associations of gene variants in the dopamine, opioid, and serotonin pathways with smoking reward (’liking’) and reinforcement (latency to first puff and total puffs) as a function of negative mood. (PMID:18690118)
• results confirm a published association between TAQ1 A (rs1800497) T allele and cognitive outcome measures 1 month after TBI and suggest that a haploblock of polymorphisms in ANKK1, not the adjacent DRD2 gene, has the highest association after TBI (PMID:18698520)
• Variants in the two 3’-ends of ANKK1 are linked to the co-regulation of risk for comorbid alcohol and drug dependence. (PMID:18828801)
• DRD2/ANKK1 gene variations and some clinical factors may predict individual response to aripiprazole (PMID:18926547)
• ANKK1 mRNA is present in four cortical regions of the adult human brain. The TaqIA genotype may modulate a subject’s susceptibility to alcohol-associated brain damage mediated by excitotoxicity. (PMID:19283474)
• Presence of at least one copy of the A1 allele was associated with significantly higher Extraversion. (PMID:19897017)
• From the results of this study the alcohol-induced negative reinforcement may explain the greater risk for alcoholism associated with the A1 allele(ANKK1). (PMID:19914044)
• This study evaluated the interaction of ANKK1, TTC12, sex, and continental ancestry in tobacco smokers. (PMID:20133381)
• This study demonestrated that the functional link between DRD2 and ANKK1 could account for the interaction in patient with schizophrenia. (PMID:20138949)
• DRD2/ANKK1 Taq IA polymorphism is not associated with early infant temperament. (PMID:20199723)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ankk1	ENSDARG00000056921
mus_musculus	Ankk1	ENSMUSG00000032257
rattus_norvegicus	Ankk1	ENSRNOG00000025037

Paralogs (1): RIPK4 (ENSG00000183421)

Protein

Protein identifiers

Ankyrin repeat and protein kinase domain-containing protein 1 — Q8NFD2 (reviewed: Q8NFD2)

Alternative names: Protein kinase PKK2, Sugen kinase 288, X-kinase

All UniProt accessions (2): Q8NFD2, H0YH32

UniProt curated annotations — full annotation on UniProt →

Tissue specificity. Highly expressed in brain and weakly expressed in placenta and spinal cord.

Similarity. Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.

RefSeq proteins (1): NP_848605* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF00023, PF07714, PF12796, PF13637

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (38 total): sequence variant 21, repeat 12, binding site 2, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NFD2-F1	81.65	0.54

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 145 (proton acceptor)

Ligand- & substrate-binding residues (2): 28–36; 51

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 36 (showing top): GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_RETINOIC_ACID, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_RETINOIC_ACID, GOBP_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_CELL_CYCLE_PROCESS, GOMF_PROTEIN_KINASE_ACTIVITY, GOMF_KINASE_ACTIVITY, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_UP, GOMF_PROTEIN_SERINE_THREONINE_KINASE_ACTIVITY, GOMF_ADENYL_NUCLEOTIDE_BINDING, GOMF_TRANSFERASE_ACTIVITY_TRANSFERRING_PHOSPHORUS_CONTAINING_GROUPS

GO Biological Process (3): regulation of cell cycle process (GO:0010564), cellular response to retinoic acid (GO:0071300), protein phosphorylation (GO:0006468)

GO Molecular Function (8): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	2
cellular anatomical structure	2
cell cycle process	1
regulation of cell cycle	1
response to retinoic acid	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
phosphorylation	1
protein modification process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1362 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANKK1	DRD2	P14416	953
ANKK1	TTC12	Q9H892	898
ANKK1	COMT	P21964	853
ANKK1	DRD4	P21917	779
ANKK1	ALDH2	P05091	777
ANKK1	SLC6A4	P31645	764
ANKK1	OPRM1	P35372	722
ANKK1	ADH1B	P00325	705
ANKK1	SLC6A3	Q01959	702
ANKK1	CHRM2	P08172	702
ANKK1	OPRD1	P41143	683
ANKK1	TAS2R16	Q9NYV7	677
ANKK1	DRD3	P35462	668
ANKK1	ADH7	P40394	641
ANKK1	TOMT	Q8WZ04	633

IntAct

23 interactions, top by confidence:

A	B	Type	Score
ANKK1	HIF1AN	psi-mi:“MI:0915”(physical association)	0.740
ANKK1	YEATS4	psi-mi:“MI:0915”(physical association)	0.670
YEATS4	ANKK1	psi-mi:“MI:0915”(physical association)	0.670
CHN2	ANKK1	psi-mi:“MI:0915”(physical association)	0.560
CHN1	ANKK1	psi-mi:“MI:0915”(physical association)	0.560
C2CD6	ANKK1	psi-mi:“MI:0915”(physical association)	0.560
ANKK1	C12orf57	psi-mi:“MI:0915”(physical association)	0.560
ANKK1	HSP90AA1	psi-mi:“MI:0914”(association)	0.530
M		psi-mi:“MI:0914”(association)	0.350
ANKK1	DNAJB6	psi-mi:“MI:0914”(association)	0.350
ANKK1	PRR14L	psi-mi:“MI:0914”(association)	0.350
ANKK1	CHN2	psi-mi:“MI:0915”(physical association)	0.000
ANKK1	CHN1	psi-mi:“MI:0915”(physical association)	0.000
C2CD6	ANKK1	psi-mi:“MI:0915”(physical association)	0.000
ANKK1	HIF1AN	psi-mi:“MI:0915”(physical association)	0.000
ANKK1	C12orf57	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (36): ANKK1 (Two-hybrid), ANKK1 (Two-hybrid), ANKK1 (Two-hybrid), ANKK1 (Two-hybrid), ANKK1 (Two-hybrid), ANKK1 (Two-hybrid), ANKK1 (Affinity Capture-MS), ANKK1 (Affinity Capture-MS), CDC37 (Affinity Capture-MS), HSP90AA4P (Affinity Capture-MS), HSP90AA1 (Affinity Capture-MS), HSP90AB1 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), HSPA1A (Affinity Capture-MS), HSPA1L (Affinity Capture-MS)

ESM2 similar proteins: A0A8C2MDK8, A0A8I6GM68, A6H751, A7YY46, A8MX76, D3YXS5, D3ZBP4, D3ZEY4, E7F9T0, E9QAM5, F1MH07, F1QCV2, F8WLE0, P16452, P23249, P48760, P49222, P52824, Q2NKY8, Q2QWU2, Q3SYT1, Q3ZBE0, Q4R380, Q50L43, Q5BJS0, Q5NCQ5, Q5R607, Q5RKI3, Q5ZI74, Q69ZP3, Q6P5E8, Q6ZSI9, Q7L2E3, Q8BX80, Q8N490, Q8NFD2, Q8NFI3, Q8TDZ2, Q8TE96, Q8VDP3

Diamond homologs: A2VDU3, C0LGF4, C0LGI2, C0LGL9, C0LGP2, C0LGT5, C0LGU1, C0LGX3, D7UPN3, F4JTP5, O22558, O43318, O43353, O80963, O81069, P0C8E4, P18161, P47735, P57078, P58801, Q05609, Q0PW40, Q0WNY5, Q13546, Q2MHE4, Q3SZJ2, Q54H45, Q54H46, Q54I36, Q54IP4, Q54M77, Q54N73, Q54QQ1, Q54RB7, Q54RR9, Q54TA1, Q54TM7, Q54XX5, Q54Y55, Q55GU0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	115
Likely benign	27
Benign	16

Top pathogenic / likely-pathogenic (0)

SpliceAI

1470 predictions. Top by Δscore:

Variant	Effect	Δscore
11:113393477:ATAGC:A	acceptor_loss	1.0000
11:113393478:T:G	acceptor_gain	1.0000
11:113393479:A:AG	acceptor_gain	1.0000
11:113393479:AG:A	acceptor_loss	1.0000
11:113393480:G:GC	acceptor_loss	1.0000
11:113393480:G:GG	acceptor_gain	1.0000
11:113393480:GCTC:G	acceptor_gain	1.0000
11:113393480:GCTCT:G	acceptor_gain	1.0000
11:113393771:TCA:T	donor_gain	1.0000
11:113393776:G:GG	donor_gain	1.0000
11:113394916:T:TA	acceptor_gain	1.0000
11:113394927:A:AG	acceptor_gain	1.0000
11:113394928:G:GG	acceptor_gain	1.0000
11:113394928:GA:G	acceptor_gain	1.0000
11:113395041:A:T	donor_gain	1.0000
11:113395077:ACAG:A	donor_loss	1.0000
11:113395078:CAGG:C	donor_loss	1.0000
11:113395079:AGG:A	donor_loss	1.0000
11:113395080:GG:G	donor_loss	1.0000
11:113395081:GT:G	donor_loss	1.0000
11:113395082:T:A	donor_loss	1.0000
11:113395357:A:AG	acceptor_gain	1.0000
11:113395358:G:GA	acceptor_gain	1.0000
11:113395358:GCTTT:G	acceptor_gain	1.0000
11:113396203:G:GT	donor_gain	1.0000
11:113396219:CTAGG:C	donor_loss	1.0000
11:113396220:TAGGT:T	donor_loss	1.0000
11:113396223:G:C	donor_loss	1.0000
11:113396224:T:G	donor_loss	1.0000
11:113397211:A:AG	acceptor_gain	1.0000

AlphaMissense

5008 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:113387930:T:C	F16L	0.928
11:113387932:C:A	F16L	0.928
11:113387932:C:G	F16L	0.928
11:113394938:T:C	F164L	0.918
11:113394940:C:A	F164L	0.918
11:113394940:C:G	F164L	0.918
11:113387993:T:C	F37L	0.899
11:113387995:C:A	F37L	0.899
11:113387995:C:G	F37L	0.899
11:113393533:T:C	F80L	0.897
11:113393535:T:A	F80L	0.897
11:113393535:T:G	F80L	0.897
11:113387945:T:C	F21L	0.893
11:113387947:C:A	F21L	0.893
11:113387947:C:G	F21L	0.893
11:113399269:T:C	F434L	0.893
11:113399271:T:A	F434L	0.893
11:113399271:T:G	F434L	0.893
11:113393692:T:C	F133L	0.887
11:113393694:C:A	F133L	0.887
11:113393694:C:G	F133L	0.887
11:113399353:T:A	W462R	0.881
11:113399353:T:C	W462R	0.881
11:113387981:T:C	F33L	0.871
11:113387983:C:A	F33L	0.871
11:113387983:C:G	F33L	0.871
11:113395360:T:C	F212L	0.870
11:113395362:T:A	F212L	0.870
11:113395362:T:G	F212L	0.870
11:113393677:A:C	S128R	0.864

dbSNP variants (sampled 300 via entrez): RS1000162738 (11:113389829 G>A), RS1000513610 (11:113389457 G>A), RS1000684821 (11:113393326 C>T), RS1000914156 (11:113387651 C>T), RS1000957717 (11:113394550 C>A,T), RS1001231499 (11:113394208 C>A), RS1001338276 (11:113387871 G>A), RS1001386697 (11:113400268 A>G), RS1001514424 (11:113395250 G>A,C), RS1001755896 (11:113400600 G>A), RS1002357219 (11:113399486 A>C), RS1003085913 (11:113388167 G>A,T), RS1003551738 (11:113392439 C>A,G), RS1003553198 (11:113397239 C>A,G), RS1003770828 (11:113398240 T>C)

Disease associations

OMIM: gene MIM:608774 | disease phenotypes: MIM:181500

GenCC curated gene-disease

Mondo (1): schizophrenia (MONDO:0005090)

Orphanet (1): NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

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

HPO	Term
HP:0100753	Schizophrenia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004860_34	Alcoholic chronic pancreatitis	6.000000e-06
GCST005951_69	Body mass index	3.000000e-10
GCST006944_51	Experiencing mood swings	5.000000e-11
GCST007328_85	Alcohol consumption (drinks per week)	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008475	mood instability measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5547 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

17 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 152,893 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL535	SUNITINIB	4	79,020
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL103667	DORAMAPIMOD	2	1,681
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1721885	SU-014813	2	363
CHEMBL215152	DEFOSBARASERTIB	2	372
CHEMBL475251	R-406	2	762
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL1908394	GSK-461364	1	1,093
CHEMBL1908397	KW-2449	1	622
CHEMBL574738	AST-487	1	451

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

PharmGKB clinical annotations

16 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1800497	Toxicity	3	nemonapride	Schizophrenia
rs1800497	Efficacy	3	disulfiram	Cocaine dependence
rs1800497	Metabolism/PK	3	olanzapine
rs1800497	Toxicity	3	valproic acid	Epilepsy
rs1800497	Efficacy	3	bupropion	Tobacco Use Disorder
rs1800497	Efficacy	3	nicotine	Tobacco Use Disorder
rs1800497	Efficacy	3	aripiprazole	Schizophrenia
rs1800497	Toxicity	3	nicotine	Tobacco Use Disorder
rs1800497	Efficacy	3	prochlorperazine	Nausea
rs1800497	Toxicity	3	opioids	Opioid-Related Disorders
rs1800497	Toxicity	3	nicotine
rs1800497	Toxicity	3	ethanol	Alcohol abuse
rs1800497	Efficacy	3	bupropion;naltrexone	Obesity
rs1800497	Toxicity	3	risperidone	Autism;Hyperprolactinemia;Schizophrenia
rs1800497	Efficacy	4	risperidone	Autism;Schizophrenia
rs7118900	Dosage	3	methadone	Heroin Dependence;Opioid-Related Disorders

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1800497	ANKK1, DRD2	3	4.50	20	risperidone;nemonapride;disulfiram;opioids;nicotine;prochlorperazine;ethanol;olanzapine;valproic acid;aripiprazole
rs2587550	ANKK1		0.00	0
rs2734849	ANKK1		0.00	0
rs4938013	ANKK1		0.00	0
rs7118900	ANKK1	3	0.00	1	methadone

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Receptor interacting protein kinase (RIPK) family

Binding affinities (BindingDB)

9 measured of 9 human assays (9 total across all organisms); most potent 9 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
Staurosporine	KD	1.7 nM
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 nM
N-[4-({4-[(3-methyl-1H-pyrazol-5-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide	KD	1100 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
2-{3-[(7-{3-[ethyl(2-hydroxyethyl)amino]propoxy}quinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide	KD	1900 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM

ChEMBL bioactivities

35 potent at pChembl≥5 of 35 total, top 25 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.50	Kd	32	nM	LESTAURTINIB
7.10	Kd	79	nM	DOVITINIB
7.09	Kd	82	nM	KW-2449
6.80	Kd	160	nM	SU-014813
6.57	Kd	270	nM	STAUROSPORINE
6.51	Kd	310	nM	SUNITINIB
6.48	Kd	330	nM	R-406
6.41	Kd	390	nM	RUXOLITINIB
6.30	Kd	500	nM	JNJ-7706621
6.20	Kd	630	nM	AST-487
6.11	Kd	780	nM	CRIZOTINIB
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
6.00	Kd	1000	nM	DORAMAPIMOD
5.85	Kd	1400	nM	CHEMBL1908395
5.82	Kd	1500	nM	DEFOSBARASERTIB
5.82	Kd	1500	nM	FORETINIB
5.68	Kd	2100	nM	BOSUTINIB
5.58	Kd	2600	nM	CHEMBL1241674
5.44	Kd	3600	nM	AXITINIB
5.37	Kd	4300	nM	FEDRATINIB
5.25	Kd	5600	nM	TOZASERTIB
5.21	Kd	6200	nM	GSK-461364
5.03	Kd	9400	nM	TAE-684

PubChem BioAssay actives

32 with measured affinity, of 171 total; 22 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507832: Binding affinity to ANKK1	kd	0.0320	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	436005: Binding constant for ANKK1 kinase domain	kd	0.0790	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624735: Binding constant for ANKK1 kinase domain	kd	0.0820	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	436005: Binding constant for ANKK1 kinase domain	kd	0.1600	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	436005: Binding constant for ANKK1 kinase domain	kd	0.2700	uM
Sunitinib	436005: Binding constant for ANKK1 kinase domain	kd	0.3100	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624735: Binding constant for ANKK1 kinase domain	kd	0.3300	uM
Ruxolitinib	624735: Binding constant for ANKK1 kinase domain	kd	0.3900	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	436005: Binding constant for ANKK1 kinase domain	kd	0.5000	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	436005: Binding constant for ANKK1 kinase domain	kd	0.6300	uM
Crizotinib	624735: Binding constant for ANKK1 kinase domain	kd	0.7800	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	436005: Binding constant for ANKK1 kinase domain	kd	1.0000	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	624735: Binding constant for ANKK1 kinase domain	kd	1.4000	uM
2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]quinazolin-4-yl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide	436005: Binding constant for ANKK1 kinase domain	kd	1.5000	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	624735: Binding constant for ANKK1 kinase domain	kd	1.5000	uM
Bosutinib	624735: Binding constant for ANKK1 kinase domain	kd	2.1000	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	624735: Binding constant for ANKK1 kinase domain	kd	2.6000	uM
Axitinib	624735: Binding constant for ANKK1 kinase domain	kd	3.6000	uM
Fedratinib	624735: Binding constant for ANKK1 kinase domain	kd	4.3000	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	436005: Binding constant for ANKK1 kinase domain	kd	5.6000	uM
5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide	624735: Binding constant for ANKK1 kinase domain	kd	6.2000	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624735: Binding constant for ANKK1 kinase domain	kd	9.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
Acetaminophen	increases expression	1
Arsenic	increases methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
N-Nitrosopyrrolidine	decreases expression	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	increases expression	1

ChEMBL screening assays

74 unique, capped per target: 74 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1032252	Binding	Inhibition of ANKK1 at 3 uM	Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety