AK4

Summary

AK4 (adenylate kinase 4, HGNC:363) is a protein-coding gene on chromosome 1p31.3, encoding Adenylate kinase 4, mitochondrial (P27144). Broad-specificity mitochondrial nucleoside phosphate kinase involved in cellular nucleotide homeostasis by catalyzing nucleoside-phosphate interconversions. It is a selective cancer dependency (DepMap: 31.0% of cell lines).

This gene encodes a member of the adenylate kinase family of enzymes. The encoded protein is localized to the mitochondrial matrix. Adenylate kinases regulate the adenine and guanine nucleotide compositions within a cell by catalyzing the reversible transfer of phosphate group among these nucleotides. Five isozymes of adenylate kinase have been identified in vertebrates. Expression of these isozymes is tissue-specific and developmentally regulated. A pseudogene for this gene has been located on chromosome 17. Three transcript variants encoding the same protein have been identified for this gene. Sequence alignment suggests that the gene defined by NM_013410, NM_203464, and NM_001005353 is located on chromosome 1.

Source: NCBI Gene 205 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 176 total — 69 pathogenic, 3 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 31.0% of screened cell lines
• MANE Select transcript: NM_013410

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:363
Approved symbol	AK4
Name	adenylate kinase 4
Location	1p31.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000162433
Ensembl biotype	protein_coding
OMIM	103030
Entrez	205

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 26 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000327299, ENST00000395334, ENST00000470888, ENST00000474968, ENST00000479060, ENST00000497030, ENST00000545314, ENST00000546702, ENST00000900806, ENST00000900807, ENST00000900808, ENST00000900809, ENST00000900810, ENST00000900811, ENST00000900812, ENST00000900813, ENST00000900814, ENST00000900815, ENST00000900816, ENST00000900817, ENST00000900818, ENST00000900819, ENST00000900820, ENST00000900821, ENST00000900822, ENST00000938014, ENST00000938015, ENST00000938016, ENST00000957443, ENST00000957444

RefSeq mRNA: 4 — MANE Select: NM_013410 NM_001005353, NM_001330616, NM_013410, NM_203464

CCDS: CCDS629, CCDS81340

Canonical transcript exons

ENST00000327299 — 5 exons

Exon	Start	End
ENSE00001173665	65226063	65232145
ENSE00001426109	65148203	65148552
ENSE00003548883	65218754	65218926
ENSE00003567811	65224752	65224870
ENSE00003644072	65190710	65190829

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 97.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.8349 / max 274.8136, expressed in 1822 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
99808	43.8349	1822
3255	5.6120	1424
3252	5.2263	1494
3253	0.7180	403
3256	0.7110	448
3257	0.6596	398
3259	0.6039	326
3254	0.3577	202
3260	0.2841	106
3258	0.2425	111

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adult organism	UBERON:0007023	97.70	gold quality
renal medulla	UBERON:0000362	97.63	gold quality
heart right ventricle	UBERON:0002080	97.39	gold quality
upper leg skin	UBERON:0004262	96.51	gold quality
pericardium	UBERON:0002407	96.07	gold quality
skin of hip	UBERON:0001554	96.03	gold quality
adult mammalian kidney	UBERON:0000082	95.72	gold quality
saphenous vein	UBERON:0007318	95.67	gold quality
mammary duct	UBERON:0001765	95.29	gold quality
esophagus squamous epithelium	UBERON:0006920	94.33	gold quality
medial globus pallidus	UBERON:0002477	93.97	gold quality
cauda epididymis	UBERON:0004360	93.88	gold quality
liver	UBERON:0002107	93.68	gold quality
nipple	UBERON:0002030	93.41	gold quality
globus pallidus	UBERON:0001875	93.27	gold quality
entorhinal cortex	UBERON:0002728	93.27	gold quality
epithelium of mammary gland	UBERON:0003244	93.07	gold quality
cardia of stomach	UBERON:0001162	93.05	gold quality
superior vestibular nucleus	UBERON:0007227	93.00	gold quality
penis	UBERON:0000989	92.91	gold quality
nephron tubule	UBERON:0001231	92.74	gold quality
kidney	UBERON:0002113	92.60	gold quality
endothelial cell	CL:0000115	92.55	gold quality
myocardium	UBERON:0002349	92.43	gold quality
epithelium of esophagus	UBERON:0001976	92.31	gold quality
substantia nigra pars compacta	UBERON:0001965	92.29	gold quality
mammalian vulva	UBERON:0000997	92.26	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.20	gold quality
cerebellar vermis	UBERON:0004720	91.89	gold quality
postcentral gyrus	UBERON:0002581	91.84	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	48.14
E-HCAD-10	yes	33.90
E-GEOD-93593	yes	14.26
E-MTAB-9388	yes	12.96
E-MTAB-8271	yes	8.92
E-MTAB-7008	no	638.66
E-MTAB-6386	no	33.81
E-ENAD-27	no	3.28
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF3

miRNA regulators (miRDB)

250 targeting AK4, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-5011-5P	100.00	83.46	5820
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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-27A-3P	99.98	72.13	2955

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 31.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• To investigate the role of hinge IV, crystal structure of human adenylate kinase 4 (AK4) L171P mutant was determined. (PMID:19073142)
• The AK4 cDNA was expressed in Escherichia coli and the substrate specificity and kinetic properties of the recombinant protein were characterized. (PMID:19766732)
• Data indicate that patients with high adenylate kinase-4 (AK4) and low transcription factor ATF3 expression showed unfavorable outcomes compared with patients with low AK4 and high ATF3 expression. (PMID:23002211)
• a stress-protective function of AK4 (PMID:23474458)
• Results found that AK4 was involved in hypoxia tolerance, resistance to anti-tumor drug, and the regulation of mitochondrial activity. (PMID:26980435)
• Our data revealed that both miR-199a-3p and its target gene AK4 are reversely correlated with the osteosarcoma drug resistance. (PMID:29866054)
• The overexpression of AK4 stabilizes HIF-1alpha protein by increasing intracellular ROS levels and induces epithelial-to-mesenchymal transition in non-small cell lung cancer. (PMID:30696468)
• 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)
• Study found that AK4 was positively correlated with poor prognosis of bladder cancer (BC) patients. Its knockdown in bladder cancer cell lines inhibited proliferation and invasion and suppressed tumor formation and metastasis in mice. AK4 may therefore represent a potential biomarker for the prognosis of bladder cancer. (PMID:31463832)
• Knockdown of circ-ABCB10 promotes sensitivity of lung cancer cells to cisplatin via miR-556-3p/AK4 axis. (PMID:31931771)
• Adenylate Kinase 4 Modulates the Resistance of Breast Cancer Cells to Tamoxifen through an m(6)A-Based Epitranscriptomic Mechanism. (PMID:32956623)
• MiR-3666 serves as a tumor suppressor in ovarian carcinoma by down-regulating AK4 via targeting STAT3. (PMID:33361582)
• Adenylate Kinase 4-A Key Regulator of Proliferation and Metabolic Shift in Human Pulmonary Arterial Smooth Muscle Cells via Akt and HIF-1alpha Signaling Pathways. (PMID:34638712)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ak4	ENSDARG00000006546
mus_musculus	Ak4	ENSMUSG00000028527
rattus_norvegicus	Ak4	ENSRNOG00000045738
drosophila_melanogaster	CG9541	FBGN0032083
caenorhabditis_elegans		WBGENE00008746

Paralogs (9): AK2 (ENSG00000004455), AK1 (ENSG00000106992), AK7 (ENSG00000140057), AK3 (ENSG00000147853), AK5 (ENSG00000154027), AK9 (ENSG00000155085), CMPK1 (ENSG00000162368), AK8 (ENSG00000165695), AK4P3 (ENSG00000233381)

Protein

Protein identifiers

Adenylate kinase 4, mitochondrial — P27144 (reviewed: P27144)

Alternative names: Adenylate kinase 3-like, GTP:AMP phosphotransferase AK4

All UniProt accessions (2): P27144, F8VS11

UniProt curated annotations — full annotation on UniProt →

Function. Broad-specificity mitochondrial nucleoside phosphate kinase involved in cellular nucleotide homeostasis by catalyzing nucleoside-phosphate interconversions. Similar to other adenylate kinases, preferentially catalyzes the phosphorylation of the nucleoside monophosphate AMP with ATP as phosphate donor to produce ADP. Phosphorylates only AMP when using GTP as phosphate donor. In vitro, can also catalyze the phosphorylation of CMP, dAMP and dCMP and use GTP as an alternate phosphate donor. Moreover, exhibits a diphosphate kinase activity, producing ATP, CTP, GTP, UTP, TTP, dATP, dCTP and dGTP from the corresponding diphosphate substrates with either ATP or GTP as phosphate donors. Plays a role in controlling cellular ATP levels by regulating phosphorylation and activation of the energy sensor protein kinase AMPK. Plays a protective role in the cellular response to oxidative stress.

Subunit / interactions. Monomer (Ref.17). Interacts with SLC25A5/ANT2.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Highly expressed in kidney, moderately expressed in heart and liver and weakly expressed in brain.

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 GTP/ATP binding. Assembling and disassembling the active center during each catalytic cycle provides an effective means to prevent GTP/ATP hydrolysis.

Induction. By hypoxia (at protein level).

Similarity. Belongs to the adenylate kinase family. AK3 subfamily.

RefSeq proteins (4): NP_001005353, NP_001317545, NP_037542, NP_982289 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000850	Adenylat/UMP-CMP_kin	Family
IPR006259	Adenyl_kin_sub	Family
IPR007862	Adenylate_kinase_lid-dom	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR028585	AK4_mitochondrial	Family
IPR028586	AK3/Ak4_mitochondrial	Family
IPR033690	Adenylat_kinase_CS	Conserved_site
IPR036193	ADK_active_lid_dom_sf	Homologous_superfamily

Pfam: PF00406, PF05191

Enzyme classification (BRENDA):

• EC 2.7.4.10 — nucleoside-triphosphate-adenylate kinase (BRENDA: 6 organisms, 49 substrates, 17 inhibitors, 13 Km, 0 kcat entries)
• EC 2.7.4.3 — adenylate kinase (BRENDA: 73 organisms, 259 substrates, 134 inhibitors, 192 Km, 47 kcat entries)

Substrate kinetics (BRENDA)

17 substrates with measured Km, best-characterized 15. 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
AMP	0.033–0.21	3
GTP	0.056–0.359	3
DAMP	0.507–2	2
ADP	0.29	1
ATP	1	1
CTP	9.1	1
GDP	0.0012	1
ITP	0.63	1
UTP	7.4	1
2’-DAMP	0.85	1
7-DEAZAADENOSINE 5’-MONOPHOSPHATE	0.73	1

Catalyzed reactions (Rhea), 12 shown:

• CMP + ATP = CDP + ADP (RHEA:11600)
• 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)
• dCMP + ATP = dCDP + ADP (RHEA:25094)
• UDP + ATP = UTP + ADP (RHEA:25098)
• CDP + ATP = CTP + ADP (RHEA:25237)
• dCDP + ATP = dCTP + ADP (RHEA:27678)
• dTDP + ATP = dTTP + ADP (RHEA:27682)
• GDP + ATP = GTP + ADP (RHEA:27686)
• dGDP + ATP = dGTP + ADP (RHEA:27690)

UniProt features (45 total): helix 11, binding site 10, strand 7, modified residue 6, turn 4, region of interest 2, mutagenesis site 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2BBW	X-RAY DIFFRACTION	2.05
2AR7	X-RAY DIFFRACTION	2.15
3NDP	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P27144-F1	91.42	0.71

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): 135–136; 170; 199; 15–20; 36; 41; 62–64; 89–92; 96; 126

Post-translational modifications (6): 60, 175, 179, 179, 186, 186

Mutagenesis-validated functional residues (2):

Position	Phenotype
4	abolishes mitochondrial import; when associated with g-7.
7	abolishes mitochondrial import; when associated with g-4.

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: 598 (showing top): RNGTGGGC_UNKNOWN, VERHAAK_AML_WITH_NPM1_MUTATED_DN, SHEPARD_BMYB_MORPHOLINO_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, HARRIS_HYPOXIA, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (13): regulation of oxidative phosphorylation (GO:0002082), ADP biosynthetic process (GO:0006172), nucleoside triphosphate biosynthetic process (GO:0009142), ribonucleoside diphosphate biosynthetic process (GO:0009188), nucleobase-containing small molecule interconversion (GO:0015949), AMP metabolic process (GO:0046033), ATP metabolic process (GO:0046034), GTP metabolic process (GO:0046039), cellular response to hypoxia (GO:0071456), 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 (15): AMP kinase activity (GO:0004017), nucleoside diphosphate kinase activity (GO:0004550), ATP binding (GO:0005524), GTP binding (GO:0005525), CMP kinase activity (GO:0036430), dCMP kinase activity (GO:0036431), nucleoside triphosphate adenylate kinase activity (GO:0046899), dAMP kinase activity (GO:0047506), nucleoside monophosphate kinase activity (GO:0050145), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), phosphotransferase activity, phosphate group as acceptor (GO:0016776), nucleobase-containing compound kinase activity (GO:0019205)

GO Cellular Component (3): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

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	3
phosphotransferase activity, phosphate group as acceptor	3
nucleobase-containing compound kinase activity	3
purine ribonucleoside triphosphate metabolic process	2
nucleoside phosphate metabolic process	2
nucleoside monophosphate kinase activity	2
purine ribonucleoside triphosphate binding	2
deoxynucleoside phosphate kinase activity, ATP as phosphate donor	2
transferase activity, transferring phosphorus-containing groups	2
oxidative phosphorylation	1
regulation of aerobic respiration	1
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
nucleoside diphosphate biosynthetic process	1
ribonucleoside diphosphate metabolic process	1
nucleobase-containing small molecule metabolic process	1
purine ribonucleoside monophosphate metabolic process	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
primary metabolic process	1
nucleoside monophosphate metabolic process	1
nucleotide biosynthetic process	1
adenyl ribonucleotide binding	1
guanyl ribonucleotide binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
kinase activity	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

3196 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AK4	NME4	O00746	780
AK4	DGUOK	P78532	721
AK4	NT5M	Q9NPB1	681
AK4	AK7	Q96M32	664
AK4	EVI2B	P34910	640
AK4	CMPK2	Q5EBM0	633
AK4	SELP	P16109	598
AK4	EVI2A	P22794	589
AK4	DTYMK	P23919	571
AK4	AK1	P00568	553
AK4	TK2	O00142	548
AK4	OMG	P23515	495
AK4	NF1	P21359	476
AK4	MAGEA3	P43357	473
AK4	GP1BA	P07359	468

IntAct

79 interactions, top by confidence:

A	B	Type	Score
PHF1	EED	psi-mi:“MI:0914”(association)	0.790
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
CCL5	C4A	psi-mi:“MI:0914”(association)	0.530
TMEM184A	SLC33A1	psi-mi:“MI:0914”(association)	0.530
NSDHL	AK4	psi-mi:“MI:0915”(physical association)	0.400
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
AK4	EPHA8	psi-mi:“MI:0915”(physical association)	0.370
AK4	CEP19	psi-mi:“MI:0915”(physical association)	0.370
AK4	KEAP1	psi-mi:“MI:0915”(physical association)	0.370
DLD	NFKBIE	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
GTF2E2	UBA6	psi-mi:“MI:0914”(association)	0.350
OXLD1	NUDT19	psi-mi:“MI:0914”(association)	0.350
ATF6B	AK4	psi-mi:“MI:0914”(association)	0.350
NDUFS3	ACOT7	psi-mi:“MI:0914”(association)	0.350
TEX101	PSMD12	psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
TAGLN	LOC392647	psi-mi:“MI:0914”(association)	0.350
rep	VWA8	psi-mi:“MI:0914”(association)	0.350
E2F1	CLIC1	psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (199): AK4 (Affinity Capture-MS), WDR45B (Affinity Capture-MS), AK4 (Affinity Capture-MS), AK4 (Affinity Capture-MS), AK4 (Affinity Capture-MS), AK4 (Affinity Capture-MS), AK4 (Affinity Capture-MS), AK4 (Affinity Capture-MS), AK4 (Affinity Capture-MS), AK4 (Affinity Capture-MS), AK4 (Affinity Capture-RNA), AK4 (Proximity Label-MS), AK4 (Proximity Label-MS), AK4 (Proximity Label-MS), AK4 (Proximity Label-MS)

ESM2 similar proteins: A0KL52, A4SLY1, B5YHP1, B7L799, G4V9S0, O04905, O17622, P00568, P00569, P00570, P00571, P05081, P08397, P08760, P12115, P19356, P20425, P22907, P25824, P27144, P29411, P30085, P35249, P39069, P40939, P43188, P69441, Q0VCP1, Q20140, Q28H12, Q325C2, Q32J54, Q4KM73, Q5R421, Q5RDZ0, Q5ZKE7, Q64520, Q6K7H2, Q7XI40, Q7ZWE9

Diamond homologs: A0B9U5, A0LK48, A0PM98, A0PXW7, A0QSH8, A1KGL4, A1KJC9, A1RRJ5, A1VEW5, A2SPM8, A3CT23, A3DND3, A3MV67, A4FYK1, A4VLZ2, A4WKL0, A4YJJ2, A5CU93, A5GQN5, A5U0B9, A5U371, A5UL61, A6USC1, A6UW32, A6VJT1, A7I5R5, A8AAI6, A9A698, A9KJH3, B0R685, B0RB59, B1GZA3, B1YAJ8, B2HCV5, B4UBC0, B6YUL3, B8D5U4, B8GKF9, B8J881, B9K8A7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 97 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial protein degradation	6	11.1×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	69
Likely pathogenic	3
Uncertain significance	84
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
144228	GRCh38/hg38 1p32.1-31.1(chr1:59760856-71578052)x1	Pathogenic
144246	GRCh38/hg38 9p24.3-23(chr9:204193-10164955)x1	Pathogenic
144441	GRCh38/hg38 9p24.3-23(chr9:204193-11277770)x1	Pathogenic
144686	GRCh38/hg38 9p24.3-23(chr9:204090-13146846)x1	Pathogenic
144714	GRCh38/hg38 1p32.1-31.2(chr1:58819605-69107108)x1	Pathogenic
146111	GRCh38/hg38 9p24.3-24.1(chr9:220253-8866675)x1	Pathogenic
146231	GRCh38/hg38 9p24.3-24.1(chr9:204193-6968724)x1	Pathogenic
146254	GRCh38/hg38 9p24.3-23(chr9:204193-10852686)x1	Pathogenic
146684	GRCh38/hg38 9p24.3-23(chr9:204104-11298187)x1	Pathogenic
146719	GRCh38/hg38 9p24.3-22.2(chr9:204193-16897580)x1	Pathogenic
147561	GRCh38/hg38 9p24.2-23(chr9:3591159-9361786)x3	Pathogenic
147623	GRCh38/hg38 9p24.2-24.1(chr9:4152060-8518353)x1	Pathogenic
147703	GRCh38/hg38 9p24.3-22.3(chr9:214367-16307944)x1	Pathogenic
148264	GRCh38/hg38 9p24.3-24.1(chr9:204104-5426099)x3	Pathogenic
148301	GRCh38/hg38 9p24.3-24.1(chr9:204104-5695507)x1	Pathogenic
148381	GRCh38/hg38 9p24.3-24.1(chr9:204104-8266492)x1	Pathogenic
148598	GRCh38/hg38 9p24.3-23(chr9:204104-14182668)x1	Pathogenic
148677	GRCh38/hg38 9p24.3-24.1(chr9:204104-7133443)x1	Pathogenic
149059	GRCh38/hg38 9p24.3-24.1(chr9:204104-5657733)x1	Pathogenic
149060	GRCh38/hg38 9p24.3-23(chr9:204104-10023901)x1	Pathogenic
150751	GRCh38/hg38 9p24.3-23(chr9:204090-9282864)x1	Pathogenic
151916	GRCh38/hg38 9p24.3-24.1(chr9:211086-7444397)x1	Pathogenic
1527476	GRCh37/hg19 9p24.3-24.1(chr9:203861-5909152)	Pathogenic
1527477	GRCh37/hg19 9p24.3-24.1(chr9:203861-7759331)	Pathogenic
1527479	GRCh37/hg19 9p24.3-23(chr9:203861-9631665)	Pathogenic
1527480	GRCh37/hg19 9p24.3-23(chr9:203861-11414732)	Pathogenic
1527484	GRCh37/hg19 9p24.3-22.3(chr9:203861-15211277)	Pathogenic
1527485	GRCh37/hg19 9p24.3-22.2(chr9:203861-16856907)	Pathogenic
152906	GRCh38/hg38 9p24.3-24.1(chr9:185579-7635806)x1	Pathogenic
152907	GRCh38/hg38 9p24.3-23(chr9:211086-11457340)x1	Pathogenic

SpliceAI

1683 predictions. Top by Δscore:

Variant	Effect	Δscore
1:65149670:A:T	donor_gain	1.0000
1:65149686:GAAT:G	donor_gain	1.0000
1:65190705:A:AG	acceptor_gain	1.0000
1:65207046:G:GT	donor_gain	1.0000
1:65218752:A:AG	acceptor_gain	1.0000
1:65218752:AG:A	acceptor_gain	1.0000
1:65218753:G:A	acceptor_loss	1.0000
1:65218753:G:GG	acceptor_gain	1.0000
1:65218753:GG:G	acceptor_gain	1.0000
1:65218753:GGTT:G	acceptor_gain	1.0000
1:65218927:G:GG	donor_gain	1.0000
1:65224746:TTGTA:T	acceptor_loss	1.0000
1:65224747:TGTA:T	acceptor_loss	1.0000
1:65224748:GTA:G	acceptor_loss	1.0000
1:65224749:TA:T	acceptor_loss	1.0000
1:65224750:A:AG	acceptor_gain	1.0000
1:65224750:AG:A	acceptor_gain	1.0000
1:65224750:AGG:A	acceptor_gain	1.0000
1:65224751:G:GC	acceptor_gain	1.0000
1:65224751:GG:G	acceptor_gain	1.0000
1:65224751:GGG:G	acceptor_gain	1.0000
1:65224751:GGGT:G	acceptor_gain	1.0000
1:65224751:GGGTA:G	acceptor_gain	1.0000
1:65224868:CAA:C	donor_gain	1.0000
1:65224869:AA:A	donor_gain	1.0000
1:65224871:G:GG	donor_gain	1.0000
1:65224871:G:T	donor_loss	1.0000
1:65224872:T:G	donor_loss	1.0000
1:65224873:G:GT	donor_loss	1.0000
1:65226114:GCCC:G	donor_gain	1.0000

AlphaMissense

1468 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:65218756:T:C	F90L	0.994
1:65218758:T:A	F90L	0.994
1:65218758:T:G	F90L	0.994
1:65218906:T:C	F140L	0.986
1:65218908:C:A	F140L	0.986
1:65218908:C:G	F140L	0.986
1:65148441:G:A	G12R	0.985
1:65148441:G:C	G12R	0.985
1:65226112:T:A	W203R	0.984
1:65226112:T:C	W203R	0.984
1:65224855:T:A	V181D	0.983
1:65190755:T:A	V64D	0.982
1:65218777:G:C	A97P	0.982
1:65226085:T:C	F194L	0.982
1:65226087:T:A	F194L	0.982
1:65226087:T:G	F194L	0.982
1:65218823:T:C	L112S	0.981
1:65148441:G:T	G12W	0.980
1:65148442:G:A	G12E	0.980
1:65226122:T:A	V206D	0.979
1:65218757:T:C	F90S	0.978
1:65226114:G:C	W203C	0.978
1:65226114:G:T	W203C	0.978
1:65226086:T:C	F194S	0.977
1:65148492:T:C	F29L	0.975
1:65148494:T:A	F29L	0.975
1:65148494:T:G	F29L	0.975
1:65224780:T:C	L156S	0.975
1:65148457:G:A	G17D	0.974
1:65190817:T:A	W85R	0.974

dbSNP variants (sampled 300 via entrez): RS1000015525 (1:65223173 GTTATTTT>G), RS1000057533 (1:65209729 T>A), RS1000072604 (1:65167254 C>A,G), RS1000146782 (1:65164026 C>A,T), RS1000151248 (1:65223482 C>T), RS1000175364 (1:65155314 A>G), RS1000226028 (1:65155591 A>G,T), RS1000238625 (1:65174342 T>C), RS1000282386 (1:65149085 G>A,C,T), RS1000286370 (1:65203119 T>C), RS1000296520 (1:65210712 A>T), RS1000357597 (1:65161142 C>G,T), RS1000413879 (1:65162550 G>A), RS1000467521 (1:65185479 G>A), RS1000536761 (1:65228727 T>G)

Disease associations

OMIM: gene MIM:103030 | disease phenotypes: MIM:158170

GenCC curated gene-disease

Mondo (2): chromosome 9p deletion syndrome (MONDO:0008013), primary ovarian failure (MONDO:0005387)

Orphanet (2): Monosomy 9p syndrome (Orphanet:261112), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000498_2	Hematological parameters	9.000000e-17
GCST000580_1	Platelet count	3.000000e-13
GCST001337_25	Platelet count	3.000000e-49
GCST001438_3	Crohn’s disease	7.000000e-09
GCST003383_9	Platelet count	5.000000e-06
GCST003918_5	Idiopathic osteonecrosis of the femoral head	3.000000e-06
GCST004610_174	White blood cell count	6.000000e-09
GCST004630_227	Mean corpuscular hemoglobin	6.000000e-23
GCST005991_93	Platelet count	4.000000e-55
GCST012299_10	Schizophrenia, bipolar disorder or major depressive disorder x sex interaction (3df)	5.000000e-06
GCST90002397_671	Mean spheric corpuscular volume	6.000000e-18

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:1001930	idiopathic osteonecrosis of the femoral head
EFO:0004527	mean corpuscular hemoglobin
EFO:0008343	sex interaction measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C538024	Chromosome 9p Deletion Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4926 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1109374	AK4		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases expression, increases methylation, affects cotreatment	9
bisphenol A	affects expression, affects cotreatment, increases methylation, decreases expression, increases expression	4
methylmercuric chloride	decreases expression, increases expression	3
cobaltous chloride	increases expression, decreases reaction	3
Acetaminophen	decreases expression	3
Cisplatin	affects expression, increases expression	3
Oxygen	decreases reaction, increases expression	3
Tretinoin	affects expression, decreases expression, increases expression	3
bisphenol F	increases expression, affects cotreatment	2
sodium arsenite	affects methylation, decreases expression, increases abundance	2
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	2
bisphenol S	increases expression, affects cotreatment, decreases methylation	2
(+)-JQ1 compound	decreases reaction, increases expression, decreases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Estradiol	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cadmium Chloride	increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
4-hydroxyphenyl 4-isopropoxyphenylsulfone	decreases expression	1
beauvericin	affects cotreatment, decreases expression	1
chloroacetaldehyde	increases expression	1
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chloride	decreases reaction, increases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
tamibarotene	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL648974	Binding	Ability to inhibit Escherichia coli adenylate kinase III, activity expressed as Inhibition constant; Non competitive inhibition	Use of adenine nucleotide derivatives to assess the potential of exo-active-site-directed reagents as species- or isozyme-specific enzyme inactivators. 4. Interactions of adenosine 5’-triphosphate derivatives with adenylate kinases from Escherichia coli and rat tissues. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1JB	Abcam HeLa AK4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT04586400	Not specified	RECRUITING	Chromosome 9 P Minus Syndrome
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure