AK1

Summary

AK1 (adenylate kinase 1, HGNC:361) is a protein-coding gene on chromosome 9q34.11, encoding Adenylate kinase isoenzyme 1 (P00568). Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP.

This gene encodes an adenylate kinase enzyme involved in energy metabolism and homeostasis of cellular adenine nucleotide ratios in different intracellular compartments. This gene is highly expressed in skeletal muscle, brain and erythrocytes. Certain mutations in this gene resulting in a functionally inadequate enzyme are associated with a rare genetic disorder causing nonspherocytic hemolytic anemia. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. This gene shares readthrough transcripts with the upstream ST6GALNAC6 gene.

Source: NCBI Gene 203 — RefSeq curated summary.

At a glance

• Gene–disease (curated): adenosine kinase deficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 22
• Clinical variants (ClinVar): 302 total — 23 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 36
• Druggable target: yes
• MANE Select transcript: NM_000476

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:361
Approved symbol	AK1
Name	adenylate kinase 1
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Aliases	ADK, Adk1
Ensembl gene	ENSG00000106992
Ensembl biotype	protein_coding
OMIM	103000
Entrez	203

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 21 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000223836, ENST00000373156, ENST00000413016, ENST00000550143, ENST00000550992, ENST00000644144, ENST00000904238, ENST00000904239, ENST00000904240, ENST00000904241, ENST00000904242, ENST00000904243, ENST00000904244, ENST00000937831, ENST00000954052, ENST00000954053, ENST00000954054, ENST00000954055, ENST00000954056, ENST00000954057, ENST00000954058, ENST00000954059, ENST00000954060, ENST00000954061

RefSeq mRNA: 3 — MANE Select: NM_000476 NM_000476, NM_001318121, NM_001318122

CCDS: CCDS6881, CCDS83419

Canonical transcript exons

ENST00000644144 — 7 exons

Exon	Start	End
ENSE00003515397	127874611	127874649
ENSE00003589468	127871823	127871939
ENSE00003590596	127868321	127868512
ENSE00003611102	127873026	127873061
ENSE00003683450	127872690	127872853
ENSE00003816290	127866486	127868076
ENSE00003824269	127877623	127877675

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 99.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.6558 / max 745.9202, expressed in 1609 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102605	28.3292	1575
102606	6.8681	1492
102607	2.7782	1281
102604	0.3801	61
102603	0.1720	67
102602	0.1281	62

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.76	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.55	gold quality
gastrocnemius	UBERON:0001388	99.50	gold quality
right uterine tube	UBERON:0001302	99.47	gold quality
heart left ventricle	UBERON:0002084	99.47	gold quality
right atrium auricular region	UBERON:0006631	99.40	gold quality
muscle of leg	UBERON:0001383	99.06	gold quality
muscle organ	UBERON:0001630	99.05	gold quality
skeletal muscle organ	UBERON:0014892	99.05	gold quality
heart	UBERON:0000948	98.95	gold quality
skeletal muscle tissue	UBERON:0001134	98.93	gold quality
hypothalamus	UBERON:0001898	98.93	gold quality
amygdala	UBERON:0001876	98.92	gold quality
substantia nigra	UBERON:0002038	98.84	gold quality
temporal lobe	UBERON:0001871	98.76	gold quality
caudate nucleus	UBERON:0001873	98.75	gold quality
Ammon’s horn	UBERON:0001954	98.69	gold quality
nucleus accumbens	UBERON:0001882	98.52	gold quality
putamen	UBERON:0001874	98.49	gold quality
anterior cingulate cortex	UBERON:0009835	98.48	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.26	gold quality
prefrontal cortex	UBERON:0000451	98.22	gold quality
cerebral cortex	UBERON:0000956	98.21	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.21	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.20	gold quality
right frontal lobe	UBERON:0002810	98.18	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.15	gold quality
frontal cortex	UBERON:0001870	98.13	gold quality
brain	UBERON:0000955	98.07	gold quality
left coronary artery	UBERON:0001626	97.99	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-38	yes	1622.85
E-HCAD-1	yes	88.21
E-ANND-3	yes	25.96
E-GEOD-125970	yes	6.32
E-MTAB-7303	no	719.04
E-MTAB-9467	no	1.47

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NEUROD1

miRNA regulators (miRDB)

53 targeting AK1, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-5589-3P	99.29	68.30	1443
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628

Literature-anchored findings (GeneRIF, showing 19)

• how mutations found in 2 patients may affect enzyme structure and function; a compound heterozygote for 2 different missense mutations 118G>A(Gly40Arg) and 190G>A(Gly64Arg); a homozygote for either aspartic acid (Asp) 140 or 141 (PMID:12649162)
• analysis of vascular endothelial ectoadenylate kinase and plasma membrane ATP synthase (PMID:16714292)
• The alpha-borano or alpha-H on PMEA and PMPA were detrimental to the activity of recombinant human AMP kinases 1 (PMID:18404568)
• The data suggest that zygotes carrying AK1*2 allele are relatively protected from the damaging effects of smoking (PMID:18850517)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• the correlation between blood glucose and glycated Hb in relation to AK1 and ACP1 polymorphism was studied. (PMID:20152999)
• The adipokine zinc-alpha2-glycoprotein activates AMP kinase in human primary skeletal muscle cells. (PMID:21457004)
• AK1 phenotypic activity is associated with birth weight and placental weight; these associations are greater in infants born at gestational age greater than 38 weeks. (PMID:21831515)
• Our findings suggest a reduced reproductive efficiency of women carrying the Ak(1)2-1 phenotype: this could have practical importance in predicting the probability of reproductive success in couples with RSA (PMID:22287021)
• Data indicate that the neuronal adenylate kinase-1 (AK1) is induced by Abeta(42) to increase abnormal tau phosphorylation via AMPK-GSK3beta and contributes to tau-mediated neurodegeneration. (PMID:22419736)
• identified hitherto unrecognized soluble forms of AK1 and NTPDase1/CD39 that contribute in the active cycling between the principal platelet-recruiting agent ADP and other circulating nucleotides (PMID:22637533)
• Ak(1)2-1 phenotype is more frequent in males conceived in the summer-autumn period than in those conceived in winter-spring, and this association depends on maternal Ak(1) phenotype. (PMID:23146316)
• Dysregulation of AMPK is both a pathogenic factor for these disorders in humans and a target for their prevention and therapy. [Review] (PMID:23863634)
• Studies indicate that the preferred substrate and phosphate donor of all adenylate kinases are AMP and ATP respectively. (PMID:24495878)
• Case Reports: first case of adenylate kinase deficiency in Indian population due to novel AK1 mutations (c.71A>G and c.413G>A) associated with nonspherocytic haemolytic anaemia without psychomotor impairment. (PMID:30918013)
• Specific DNA methylation signatures for aggressive choroid plexus carcinoma (CPC) revealed AK1, PER2, and PLSCR4 as potential biomarkers for CPC that can be used to improve molecular stratification for diagnosis and treatment. (PMID:31409384)
• A co-expressed gene status of adenylate kinase 1/4 reveals prognostic gene signature associated with prognosis and sensitivity to EGFR targeted therapy in lung adenocarcinoma. (PMID:31444368)
• The mRNA and protein expressions of AK1, AK6 and AK7 are significantly down-regulated in the sperm of asthenospermia patients, which may be closely related with reduced sperm motility. (PMID:32251557)
• High expression of AK1 predicts inferior prognosis in acute myeloid leukemia patients undergoing chemotherapy. (PMID:32519744)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ak1	ENSDARG00000001950
mus_musculus	Ak1	ENSMUSG00000026817
rattus_norvegicus	Ak1	ENSRNOG00000049056
caenorhabditis_elegans		WBGENE00009531

Paralogs (9): AK2 (ENSG00000004455), AK7 (ENSG00000140057), AK3 (ENSG00000147853), AK5 (ENSG00000154027), AK9 (ENSG00000155085), CMPK1 (ENSG00000162368), AK4 (ENSG00000162433), AK8 (ENSG00000165695), AK4P3 (ENSG00000233381)

Protein

Protein identifiers

Adenylate kinase isoenzyme 1 — P00568 (reviewed: P00568)

Alternative names: ATP-AMP transphosphorylase 1, ATP:AMP phosphotransferase, Adenylate monophosphate kinase, Myokinase

All UniProt accessions (5): P00568, F8VRY5, H0YID2, Q5T9B7, Q6FGX9

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. Also displays broad nucleoside diphosphate kinase activity. Plays an important role in cellular energy homeostasis and in adenine nucleotide metabolism. Also catalyzes at a very low rate the synthesis of thiamine triphosphate (ThTP) from thiamine diphosphate (ThDP) and ADP.

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm.

Disease relevance. Anemia, congenital, non-spherocytic hemolytic, 3 (CNSHA3) [MIM:612631] An autosomal recessive disease characterized by hemolytic anemia and undetectable erythrocyte adenylate kinase activity. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Consists of three domains, a large central CORE domain and two small peripheral domains, NMPbind and LID, which undergo movements during catalysis. The LID domain closes over the site of phosphoryl transfer upon ATP binding. Assembling and disassembling the active center during each catalytic cycle provides an effective means to prevent ATP hydrolysis.

Polymorphism. This enzyme represents the most common of at least five alleles.

Similarity. Belongs to the adenylate kinase family. AK1 subfamily.

RefSeq proteins (3): NP_000467, NP_001305050, NP_001305051 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000850	Adenylat/UMP-CMP_kin	Family
IPR006267	AK1/5	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR028582	AK1	Family
IPR033690	Adenylat_kinase_CS	Conserved_site

Pfam: PF00406

Enzyme classification (BRENDA):

• EC 2.7.4.3 — adenylate kinase (BRENDA: 73 organisms, 259 substrates, 134 inhibitors, 192 Km, 47 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
AMP	0.0014–1.9	59
ATP	0.0001–7	58
ADP	0.003–16.8	27
2 ADP	0.006–0.15	5
DAMP	0.507–2	2
2’-DAMP	0.85	1
7-DEAZAADENOSINE 5’-MONOPHOSPHATE	0.73	1
ADP3-	0.03	1
CMP	0.0002	1

Catalyzed reactions (Rhea), 12 shown:

• AMP + ATP = 2 ADP (RHEA:12973)
• a ribonucleoside 5’-diphosphate + ATP = a ribonucleoside 5’-triphosphate + ADP (RHEA:18113)
• dAMP + ATP = dADP + ADP (RHEA:23100)
• a ribonucleoside 5’-phosphate + ATP = a ribonucleoside 5’-diphosphate + ADP (RHEA:24036)
• UDP + ATP = UTP + ADP (RHEA:25098)
• GDP + ATP = GTP + ADP (RHEA:27686)
• dGDP + ATP = dGTP + ADP (RHEA:27690)
• a 2’-deoxyribonucleoside 5’-diphosphate + ATP = a 2’-deoxyribonucleoside 5’-triphosphate + ADP (RHEA:44640)
• thiamine diphosphate + ADP = thiamine triphosphate + AMP (RHEA:69180)
• dAMP + dATP = 2 dADP (RHEA:78311)
• CDP + GTP = CTP + GDP (RHEA:79859)
• GTP + UDP = UTP + GDP (RHEA:79863)

UniProt features (42 total): helix 11, binding site 10, sequence variant 6, strand 6, sequence conflict 3, region of interest 2, modified residue 2, chain 1, turn 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2C95	X-RAY DIFFRACTION	1.71
1Z83	X-RAY DIFFRACTION	1.9
7DE3	X-RAY DIFFRACTION	2.2
7X7S	SOLUTION NMR
8X1G	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00568-F1	95.82	0.94

Functional residue map

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

Ligand- & substrate-binding residues (10): 138; 149; 177; 18–23; 39; 44; 65–67; 94–97; 101; 132

Post-translational modifications (2): 1, 38

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-499943	Interconversion of nucleotide di- and triphosphates
R-HSA-1430728	Metabolism
R-HSA-15869	Metabolism of nucleotides

MSigDB gene sets: 562 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, RNGTGGGC_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, MODULE_56, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS

GO Biological Process (9): ADP biosynthetic process (GO:0006172), nucleoside triphosphate biosynthetic process (GO:0009142), nucleobase-containing small molecule interconversion (GO:0015949), AMP metabolic process (GO:0046033), ATP metabolic process (GO:0046034), nucleobase-containing compound metabolic process (GO:0006139), nucleotide metabolic process (GO:0009117), nucleoside monophosphate metabolic process (GO:0009123), nucleoside monophosphate phosphorylation (GO:0046940)

GO Molecular Function (10): AMP kinase activity (GO:0004017), nucleoside diphosphate kinase activity (GO:0004550), ATP binding (GO:0005524), dAMP kinase activity (GO:0047506), nucleotide binding (GO:0000166), kinase activity (GO:0016301), transferase activity (GO:0016740), phosphotransferase activity, phosphate group as acceptor (GO:0016776), nucleobase-containing compound kinase activity (GO:0019205), nucleoside monophosphate kinase activity (GO:0050145)

GO Cellular Component (5): outer dense fiber (GO:0001520), cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062), sperm flagellum (GO:0036126)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of nucleotides	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
purine ribonucleotide metabolic process	2
nucleoside phosphate metabolic process	2
phosphotransferase activity, phosphate group as acceptor	2
nucleobase-containing compound kinase activity	2
transferase activity, transferring phosphorus-containing groups	2
cellular anatomical structure	2
purine ribonucleotide biosynthetic process	1
purine ribonucleoside diphosphate biosynthetic process	1
ADP metabolic process	1
nucleoside triphosphate metabolic process	1
nucleoside phosphate biosynthetic process	1
nucleobase-containing small molecule metabolic process	1
purine ribonucleoside monophosphate metabolic process	1
purine ribonucleoside triphosphate metabolic process	1
primary metabolic process	1
nucleoside monophosphate metabolic process	1
nucleotide biosynthetic process	1
nucleoside monophosphate kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
deoxynucleoside phosphate kinase activity, ATP as phosphate donor	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
kinase activity	1
sperm flagellum	1
polymeric cytoskeletal fiber	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1
9+2 motile cilium	1

Protein interactions and networks

STRING

3412 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AK1	ASS1	P00966	787
AK1	PGM1	P36871	761
AK1	AK7	Q96M32	750
AK1	ENTPD5	O75356	746
AK1	LMX1B	O60663	739
AK1	TCN2	P20062	702
AK1	GLO1	P78375	702
AK1	ALAD	P13716	683
AK1	AMPD1	P23109	665
AK1	COL5A1	P20908	658
AK1	ADK	P55263	657
AK1	ENTPD3	O75355	649
AK1	TSFM	P43897	649
AK1	KARS1	Q15046	614
AK1	ORM1	P02763	597

IntAct

38 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
OR2K2	NME2P1	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
AK1	HNRNPU	psi-mi:“MI:0915”(physical association)	0.400
TERF1	AK1	psi-mi:“MI:0915”(physical association)	0.370
AK1	TERF2IP	psi-mi:“MI:0915”(physical association)	0.370
TINF2	AK1	psi-mi:“MI:0915”(physical association)	0.370
AK1	PCNA	psi-mi:“MI:0915”(physical association)	0.370
AK1	NBAS	psi-mi:“MI:0914”(association)	0.350
HTRA4	PSMD12	psi-mi:“MI:0914”(association)	0.350
MAPT	SEPTIN8	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
SAR1B	UBA6	psi-mi:“MI:0914”(association)	0.350
VAMP8	SCAMP1	psi-mi:“MI:0914”(association)	0.350
GTF2E2	STX7	psi-mi:“MI:0914”(association)	0.350
ABTB2	IFT56	psi-mi:“MI:0914”(association)	0.350
TM4SF20	AK1	psi-mi:“MI:0914”(association)	0.350
MFGE8	MYH7B	psi-mi:“MI:0914”(association)	0.350
MRPS23	MYH7B	psi-mi:“MI:0914”(association)	0.350
NPPB	ACOT7	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350
SNRNP27	BPNT1	psi-mi:“MI:0914”(association)	0.350

BioGRID (76): AK1 (Affinity Capture-RNA), DECR1 (Affinity Capture-MS), MRE11A (Affinity Capture-MS), SLC12A2 (Affinity Capture-MS), TIA1 (Affinity Capture-MS), OGT (Affinity Capture-MS), SUCLG2 (Affinity Capture-MS), CD2BP2 (Affinity Capture-MS), COBLL1 (Affinity Capture-MS), RAB11FIP2 (Affinity Capture-MS), GEMIN5 (Affinity Capture-MS), PCF11 (Affinity Capture-MS), NBAS (Affinity Capture-MS), KDM3B (Affinity Capture-MS), BUD13 (Affinity Capture-MS)

ESM2 similar proteins: A7ZIN4, A7ZXD2, B1IZC0, B1LJN2, B1XFR1, B2U4S7, B4F1Q2, B6I0C6, B7L799, B7LV13, B7M3W6, B7N927, B7NIF6, C4ZUS8, G4V9S0, O04905, O17622, P00568, P00569, P00570, P00571, P05081, P12115, P15700, P20425, P25824, P30085, P39069, P43188, P69441, P69442, Q0T7B1, Q20140, Q20230, Q28H12, Q29561, Q2KIW9, Q325C2, Q32J54, Q3Z4S5

Diamond homologs: A0ALU7, A0RQ72, A1VYZ9, A2BTB8, A2BYR7, A3PF28, A4J592, A4QBP4, A5GIS6, A5GVX9, A6L0Z9, A6Q322, A6QAE9, A7GXF6, A7H4H3, A7HWT2, A7I057, A7IPP9, A7ZEH4, A8FL60, A8G742, A9BCM8, B0RP52, B1MVZ4, B1VEX6, B2FT48, B2RIY8, B2UTK9, B4SI37, B5E6H6, B5Z6Y9, B8DB29, B9KFZ2, B9L9Y8, C0R000, C1KZF9, C3PL31, C4LL05, G4V9S0, O04905

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	11
Uncertain significance	116
Likely benign	89
Benign	31

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070851	NC_000009.11:g.(?130577951)(130700109_?)del	Pathogenic
1162194	NM_000476.3(AK1):c.301C>A (p.Gln101Lys)	Pathogenic
1340206	GRCh37/hg19 9q33.3-34.11(chr9:128523763-132604808)x3	Pathogenic
148721	GRCh38/hg38 9q33.3-34.11(chr9:125055865-128637946)x1	Pathogenic
18263	NM_000476.3(AK1):c.382C>T (p.Arg128Trp)	Pathogenic
18265	NM_000476.3(AK1):c.491A>G (p.Tyr164Cys)	Pathogenic
18266	NM_000476.3(AK1):c.118G>A (p.Gly40Arg)	Pathogenic
18267	NM_000476.3(AK1):c.190G>A (p.Gly64Arg)	Pathogenic
18268	NM_000476.3(AK1):c.418GAC[1] (p.Asp141del)	Pathogenic
2031084	NM_006721.4(ADK):c.328_331del (p.Asp110fs)	Pathogenic
2423733	NC_000010.10:g.(?75936631)(76468203_?)del	Pathogenic
2425795	NC_000010.10:g.(?76349020)(78317046_?)del	Pathogenic
29603	NM_006721.4(ADK):c.953C>A (p.Ala318Glu)	Pathogenic
29604	NM_006721.4(ADK):c.704A>C (p.Asp235Ala)	Pathogenic
29605	NM_006721.4(ADK):c.89G>A (p.Gly30Glu)	Pathogenic
3245119	NC_000009.11:g.(?130374683)(131329276_?)del	Pathogenic
3775248	NM_006721.4(ADK):c.647_651del (p.Ala216fs)	Pathogenic
395153	GRCh37/hg19 10q22.2-22.3(chr10:75542067-79428995)x1	Pathogenic
4279231	GRCh37/hg19 9q33.3-34.11(chr9:128111120-133279576)x1	Pathogenic
4846736	GRCh38/hg38 9q33.3-34.11(chr9:126778711-128563751)x1	Pathogenic
58745	GRCh38/hg38 10q22.1-22.2(chr10:72720628-75612374)x1	Pathogenic
59125	GRCh38/hg38 9q33.3-34.11(chr9:125993583-129682375)x1	Pathogenic
983307	GRCh37/hg19 9q33.3-34.11(chr9:128512347-130702572)x1	Pathogenic
1175800	NM_000476.3(AK1):c.395G>A (p.Arg132His)	Likely pathogenic
18264	NM_000476.3(AK1):c.319C>T (p.Arg107Ter)	Likely pathogenic
2584480	NM_006721.4(ADK):c.642_645del (p.Ser215fs)	Likely pathogenic
2584481	NM_006721.4(ADK):c.916C>T (p.Gln306Ter)	Likely pathogenic
3244961	NC_000010.10:g.(?76360117)(76360271_?)dup	Likely pathogenic
3597273	NM_006721.4(ADK):c.-10_4del (p.Met1fs)	Likely pathogenic
3597287	NM_006721.4(ADK):c.569_570del (p.Thr190fs)	Likely pathogenic

SpliceAI

896 predictions. Top by Δscore:

Variant	Effect	Δscore
9:127868318:CACCT:C	donor_loss	1.0000
9:127868319:AC:A	donor_loss	1.0000
9:127868320:CCTT:C	donor_loss	1.0000
9:127868513:C:CC	acceptor_gain	1.0000
9:127871818:CTTA:C	donor_loss	1.0000
9:127871819:TTA:T	donor_loss	1.0000
9:127871820:TACCC:T	donor_loss	1.0000
9:127871821:A:AC	donor_gain	1.0000
9:127871821:AC:A	donor_gain	1.0000
9:127871821:ACCC:A	donor_loss	1.0000
9:127871822:C:CC	donor_gain	1.0000
9:127871822:CC:C	donor_gain	1.0000
9:127871822:CCCG:C	donor_gain	1.0000
9:127871822:CCCGT:C	donor_gain	1.0000
9:127871935:GTCTC:G	acceptor_gain	1.0000
9:127871937:CTC:C	acceptor_gain	1.0000
9:127871938:TC:T	acceptor_gain	1.0000
9:127871939:CC:C	acceptor_gain	1.0000
9:127871940:C:CC	acceptor_gain	1.0000
9:127871946:C:CT	acceptor_gain	1.0000
9:127871948:C:CT	acceptor_gain	1.0000
9:127871949:A:T	acceptor_gain	1.0000
9:127871951:C:CT	acceptor_gain	1.0000
9:127871952:A:T	acceptor_gain	1.0000
9:127873060:CT:C	acceptor_gain	1.0000
9:127873062:C:CC	acceptor_gain	1.0000
9:127874610:C:CG	donor_loss	1.0000
9:127874647:GCTCT:G	acceptor_loss	1.0000
9:127874648:CT:C	acceptor_gain	1.0000
9:127874650:CTGTA:C	acceptor_loss	1.0000

AlphaMissense

1243 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:127872834:C:A	K21N	1.000
9:127872834:C:G	K21N	1.000
9:127868415:T:A	D141V	0.999
9:127868415:T:G	D141A	0.999
9:127868416:C:G	D141H	0.999
9:127868425:G:T	R138S	0.999
9:127871860:G:T	P96Q	0.999
9:127871861:G:A	P96S	0.999
9:127871867:C:G	G94R	0.999
9:127872778:C:T	G40E	0.999
9:127872822:A:C	C25W	0.999
9:127872835:T:A	K21M	0.999
9:127872836:T:G	K21Q	0.999
9:127872838:C:T	G20E	0.999
9:127872844:C:T	G18D	0.999
9:127868414:G:C	D141E	0.998
9:127868414:G:T	D141E	0.998
9:127868417:G:C	D140E	0.998
9:127868417:G:T	D140E	0.998
9:127868418:T:A	D140V	0.998
9:127868419:C:G	D140H	0.998
9:127868424:C:G	R138P	0.998
9:127868451:A:G	L129P	0.998
9:127868454:C:G	R128P	0.998
9:127871866:C:A	G94V	0.998
9:127871866:C:T	G94D	0.998
9:127871867:C:A	G94C	0.998
9:127871869:T:A	D93V	0.998
9:127871870:C:G	D93H	0.998
9:127871872:A:T	I92N	0.998

dbSNP variants (sampled 300 via entrez): RS1000015594 (9:127867118 C>T), RS1000279446 (9:127872309 G>A,C), RS1000334867 (9:127872620 T>C), RS1000601421 (9:127867349 C>A), RS1000954207 (9:127877246 C>A,G), RS1001006667 (9:127877481 C>A,T), RS1001170850 (9:127876898 G>A), RS1001424780 (9:127876656 C>CCCCCCA,CT), RS1001476472 (9:127871411 C>A), RS1001601607 (9:127866235 T>A,C), RS1001623591 (9:127877149 G>C), RS1002178492 (9:127875054 G>A,C), RS1002339922 (9:127867735 C>T), RS1002389587 (9:127870568 G>A), RS1002842851 (9:127875401 G>GC)

Disease associations

OMIM: gene MIM:103000 | disease phenotypes: MIM:187300, MIM:612631, MIM:611094, MIM:614300, MIM:606170, MIM:616346, MIM:161200, MIM:612164

GenCC curated gene-disease

Disease	Classification	Inheritance
hemolytic anemia due to adenylate kinase deficiency	Strong	Autosomal recessive
adenosine kinase deficiency	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
adenosine kinase deficiency	Definitive	AR

Mondo (9): hereditary hemorrhagic telangiectasia (MONDO:0019180), hemolytic anemia due to adenylate kinase deficiency (MONDO:0012967), adenosine kinase deficiency (MONDO:0100255), genitopatellar syndrome (MONDO:0011640), developmental and epileptic encephalopathy, 31A (MONDO:0014598), developmental and epileptic encephalopathy (MONDO:0100620), intellectual disability (MONDO:0001071), nail-patella syndrome (MONDO:0008061), developmental and epileptic encephalopathy, 4 (MONDO:0012812)

Orphanet (11): Hereditary hemorrhagic telangiectasia (Orphanet:774), Hemolytic anemia due to adenylate kinase deficiency (Orphanet:86817), Hypermethioninemia encephalopathy due to adenosine kinase deficiency (Orphanet:289290), Autosomal recessive non-syndromic intellectual disability (Orphanet:88616), Genitopatellar syndrome (Orphanet:85201), Lennox-Gastaut syndrome (Orphanet:2382), Early infantile developmental and epileptic encephalopathy (Orphanet:1934), Nail-patella syndrome (Orphanet:2614), Dravet syndrome (Orphanet:33069), STXBP1-related encephalopathy (Orphanet:599373), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000256	Macrocephaly
HP:0000316	Hypertelorism
HP:0000407	Sensorineural hearing impairment
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001324	Muscle weakness
HP:0001396	Cholestasis
HP:0001397	Hepatic steatosis
HP:0001508	Failure to thrive
HP:0001642	Pulmonic stenosis
HP:0001680	Coarctation of aorta
HP:0001684	Secundum atrial septal defect
HP:0001786	Narrow foot
HP:0001878	Hemolytic anemia
HP:0002007	Frontal bossing
HP:0002059	Cerebral atrophy
HP:0002465	Poor speech
HP:0002904	Hyperbilirubinemia
HP:0003202	Skeletal muscle atrophy
HP:0003235	Hypermethioninemia
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0003676	Progressive
HP:0006580	Portal fibrosis
HP:0008151	Prolonged prothrombin time
HP:0010841	Multifocal epileptiform discharges
HP:0011344	Severe global developmental delay

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST001221_1	Permanent tooth development	6.000000e-18
GCST002030_4	Primary tooth development (time to first tooth eruption)	2.000000e-08
GCST002031_4	Primary tooth development (number of teeth)	8.000000e-16
GCST002563_21	Hypospadias	1.000000e-07
GCST003088_3	Soluble interleukin-2 receptor subunit alpha	8.000000e-06
GCST004601_118	Red blood cell count	1.000000e-10
GCST004604_50	Hematocrit	2.000000e-17
GCST004615_63	Hemoglobin concentration	2.000000e-18
GCST005951_65	Body mass index	5.000000e-09
GCST006479_28	Diverticular disease	3.000000e-06
GCST006585_2670	Blood protein levels	1.000000e-07
GCST007267_4	Systolic blood pressure	3.000000e-13
GCST007630_1	Drug experimentation measurement	4.000000e-08
GCST008309_5	Cardiac troponin-I levels	3.000000e-09
GCST010002_291	Refractive error	2.000000e-09
GCST010083_132	Hemoglobin levels	4.000000e-34
GCST010396_121	Gut microbiota (bacterial taxa, hurdle binary method)	8.000000e-07
GCST010988_443	Adult body size	3.000000e-11
GCST90002388_565	Lymphocyte count	4.000000e-12
GCST90002400_710	Plateletcrit	6.000000e-11
GCST90002402_121	Platelet count	2.000000e-10
GCST90002403_618	Red blood cell count	4.000000e-22

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0007650	soluble interleukin-2 receptor subunit alpha measurement
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004340	body mass index
EFO:0009959	diverticular disease
EFO:0006335	systolic blood pressure
EFO:0007010	drug use measurement
EFO:0010071	cardiac troponin I measurement
EFO:0007874	gut microbiome measurement
EFO:0004587	lymphocyte count
EFO:0007985	platelet crit
EFO:0004309	platelet count

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009261	Nail-Patella Syndrome	C05.550.629; C16.131.077.606; C16.320.600; C17.800.529.400
D013683	Telangiectasia, Hereditary Hemorrhagic	C14.907.454.900; C14.907.823.780; C15.378.463.515.900; C16.131.240.850.968
C567228	Adenylate Kinase Deficiency, Hemolytic Anemia Due To (supp.)
C567404	Epileptic Encephalopathy, Early Infantile, 4 (supp.)
C565255	Genitopatellar Syndrome (supp.)
C567015	Mental Retardation, Autosomal Recessive 8 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4925 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects cotreatment, increases expression	3
Valproic Acid	affects expression, increases expression	3
Benzo(a)pyrene	increases expression	2
Aflatoxin B1	increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
decamethrin	increases activity	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
1,10-phenanthroline	decreases expression	1
cobalt sulfate	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
nutlin 3	increases secretion, affects cotreatment, increases expression	1
beta-hydroxy simvastatin acid	decreases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	decreases expression	1
Acetaminophen	increases expression	1
Atrazine	decreases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Benztropine	decreases expression	1
Cannabidiol	affects cotreatment, decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3378151	Binding	Activity of recombinant AK1 (unknown origin) assessed as ADP formation by spectroscopic pyruvate kinase/lactate dehydrogenase coupled assay	Synthesis of {[5-(adenin-9-yl)-2-furyl]methoxy}methyl phosphonic acid and evaluations against human adenylate kinases. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1JA	Abcam HeLa AK1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02389959	PHASE4	COMPLETED	Intranasal Bevacizumab for HHT-Related Epistaxis
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00004654	PHASE3	COMPLETED	Phase III Randomized, Placebo-Controlled, Crossover Study of Soy Protein Isolate for Hereditary Hemorrhagic Telangiectasia
NCT00355108	PHASE3	COMPLETED	ATERO : A Randomised Study With Tranexamic Acid in Epistaxis of Rendu Osler Syndrome
NCT01031992	PHASE3	COMPLETED	Tranexamic Acid and Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)
NCT02963129	PHASE3	UNKNOWN	Treatment of Nasal Staphylococcus Aureus Colonization in Patients With HHT
NCT03227263	PHASE3	COMPLETED	BABH Study: Efficacy and Safety of Bevacizumab on Severe Bleedings Associated With Hemorrhagic Hereditary Telangiectasia (HHT).
NCT04113187	PHASE3	COMPLETED	Propranolol for Epistaxis in Hereditary Hemorrhagic Telangiectasia Patients
NCT03347526	PHASE3	SUSPENDED	A Novel Approach to Infantile Spasms
NCT03421496	PHASE3	TERMINATED	A Study to Assess Cannabidiol Oral Solution With Vigabatrin as Initial Therapy in Participants With Infantile Spasms
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00004327	PHASE2	COMPLETED	Phase II Pilot Study of Octreotide, a Somatostatin Octapeptide Analog, for Gastrointestinal Hemorrhage in Hormone-Refractory Hereditary Hemorrhagic Telangiectasia and Senile Ectasia
NCT00375622	PHASE2	COMPLETED	Anti-Estrogen Therapy for Hereditary Hemorrhagic Telangiectasia A Double-Blind Placebo-Controlled Clinical Trial
NCT00389935	PHASE2	COMPLETED	Thalidomide Reduces Arteriovenous Malformation Related Gastrointestinal Bleeding
NCT01314274	PHASE2	COMPLETED	Intranasal Submucosal Bevacizumab for Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)
NCT01397695	PHASE2	COMPLETED	Topical Bevacizumab for the Management of Recurrent Epistaxis in Patients With Hereditary Hemorrhagic Telangiectasia (HHT)
NCT01402531	PHASE2	COMPLETED	Submucosal Bevacizumab for the Management of Recurrent Epistaxis in Patients With Hereditary Hemorrhagic Telangiectasia (HHT)
NCT01408030	PHASE2	COMPLETED	North American Study of Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)
NCT01485224	PHASE2	COMPLETED	Efficacy of Thalidomide in the Treatment of Hereditary Hemorrhagic Telangiectasia
NCT02204371	PHASE2	TERMINATED	Evaluation of Pazopanib on Bleeding in Subjects With Hereditary Haemorrhagic Telangiectasia
NCT02484716	PHASE2	COMPLETED	Efficacy of a Timolol Nasal Spray as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) - (TEMPO)
NCT02874326	PHASE2	UNKNOWN	Octreotide in Patients With GI Bleeding Due to Rendu-Osler-Weber
NCT03397004	PHASE2	COMPLETED	Doxycycline for Hereditary Hemorrhagic Telangiectasia
NCT03910244	PHASE2	COMPLETED	Pomalidomide for the Treatment of Bleeding in HHT
NCT03954782	PHASE2	COMPLETED	Efficacy of Nintedanib Per os as a Treatment for Epistaxis in HHT Disease.
NCT04139018	PHASE2	COMPLETED	Timolol Gel for Epistaxis in Hereditary Hemorrhagic Telangiectasia
NCT04404881	PHASE2	ACTIVE_NOT_RECRUITING	Bevacizumab In Hereditary Hemorrhagic Telangiectasia
NCT04646356	PHASE2	COMPLETED	Tacrolimus Trial for Hereditary Hemorrhagic Telangiectasia (HHT)
NCT04976036	PHASE2	RECRUITING	Efficacy of Nintedanib for Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) Patients
NCT05269849	PHASE2	COMPLETED	Sirolimus for Nosebleeds in HHT
NCT04289467	PHASE2	RECRUITING	Treatment of Refractory Infantile Spasms With Fenfluramine
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis