AGK

Summary

AGK (acylglycerol kinase, HGNC:21869) is a protein-coding gene on chromosome 7q34, encoding Acylglycerol kinase, mitochondrial (Q53H12). Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively.

The protein encoded by this gene is a mitochondrial membrane protein involved in lipid and glycerolipid metabolism. The encoded protein is a lipid kinase that catalyzes the formation of phosphatidic and lysophosphatidic acids. Defects in this gene have been associated with mitochondrial DNA depletion syndrome 10.

Source: NCBI Gene 55750 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 432 total — 40 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 40
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_018238

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21869
Approved symbol	AGK
Name	acylglycerol kinase
Location	7q34
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10842
Ensembl gene	ENSG00000006530
Ensembl biotype	protein_coding
OMIM	610345
Entrez	55750

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 25 protein_coding, 7 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000465241, ENST00000473247, ENST00000473884, ENST00000492693, ENST00000494053, ENST00000494688, ENST00000495028, ENST00000496273, ENST00000496784, ENST00000629555, ENST00000647568, ENST00000647898, ENST00000648068, ENST00000648395, ENST00000648489, ENST00000648690, ENST00000649014, ENST00000649286, ENST00000649365, ENST00000649538, ENST00000649790, ENST00000649914, ENST00000650006, ENST00000650365, ENST00000650547, ENST00000909101, ENST00000909102, ENST00000909103, ENST00000909104, ENST00000909105, ENST00000909106, ENST00000909107, ENST00000909108, ENST00000912226, ENST00000912227, ENST00000912228, ENST00000912229, ENST00000962104, ENST00000962105, ENST00000962106

RefSeq mRNA: 2 — MANE Select: NM_018238 NM_001364948, NM_018238

CCDS: CCDS5865, CCDS94220

Canonical transcript exons

ENST00000575872 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 91.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.8831 / max 86.1217, expressed in 1694 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
81535	5.8831	1694

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	91.09	gold quality
cerebellar hemisphere	UBERON:0002245	90.37	gold quality
cerebellar cortex	UBERON:0002129	90.26	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.24	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.13	gold quality
prefrontal cortex	UBERON:0000451	89.61	gold quality
cortical plate	UBERON:0005343	89.60	gold quality
islet of Langerhans	UBERON:0000006	89.27	gold quality
bone marrow cell	CL:0002092	88.85	gold quality
right frontal lobe	UBERON:0002810	88.41	gold quality
colonic epithelium	UBERON:0000397	88.35	gold quality
calcaneal tendon	UBERON:0003701	88.25	gold quality
smooth muscle tissue	UBERON:0001135	88.22	gold quality
sural nerve	UBERON:0015488	88.14	gold quality
anterior cingulate cortex	UBERON:0009835	88.07	gold quality
right atrium auricular region	UBERON:0006631	87.77	gold quality
ganglionic eminence	UBERON:0004023	87.57	gold quality
right adrenal gland cortex	UBERON:0035827	87.44	gold quality
lower esophagus mucosa	UBERON:0035834	87.26	gold quality
right uterine tube	UBERON:0001302	87.15	gold quality
minor salivary gland	UBERON:0001830	87.14	gold quality
right adrenal gland	UBERON:0001233	87.04	gold quality
rectum	UBERON:0001052	86.95	gold quality
cerebellum	UBERON:0002037	86.83	gold quality
metanephros cortex	UBERON:0010533	86.78	gold quality
left adrenal gland	UBERON:0001234	86.72	gold quality
granulocyte	CL:0000094	86.67	gold quality
apex of heart	UBERON:0002098	86.66	gold quality
cardiac atrium	UBERON:0002081	86.57	gold quality
heart left ventricle	UBERON:0002084	86.47	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.10

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

89 targeting AGK, 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-3646	100.00	73.56	5283
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 31)

• identification and characterization of a novel lipid kinase that phosphorylates multiple substrates, MuLK (PMID:15252046)
• The chiral specificity of diacylglycerol kinase alpha, zeta & epsilon mimics the substrate specificity, with MuLK being the least selective and the epsilon isoform of diacylglycerol kinase exhibiting the greatest selectivity. (PMID:18004883)
• High Expression of acylglycerol kinase is associated with development and progression of prostate cancer. (PMID:19549252)
• Recessive mutations in AGK cause mitochondrial DNA depletion (PMID:22277967)
• Lack of the AGK causes Sengers syndrome (PMID:22284826)
• The loss of AGK led to a decrease of the adenine nucleotide translocator in the inner mitochondrial membrane in muscle. (PMID:22284826)
• This is the first mutation in AGK gene to be implicated in the development of isolated cataract. (PMID:22415731)
• Our findings suggest that ATX-AGK-LPA signaling axis might be an important player in the development and progression of diabetic retinopathy. (PMID:22864860)
• study reports 2 families with Sengers syndrome and mutations in the acylglycerol kinase gene; 1 proband had abnormal mitochondria with citrate synthase crystals, associated with high citrate synthase activity; these pedigrees confirm that mutation of AGK is responsible for the severe neonatal presentation of Sengers syndrome (PMID:23266196)
• AGK expression was significantly correlated with JAK2/STAT3 hyperactivation in esophageal squamous cell carcinoma, as well as in lung and breast cancer. (PMID:23676499)
• AGK promotes cell proliferation and tumorigenicity in breast cancer via suppression of the FOXO1. (PMID:24886245)
• compare our findings to those in 21 previously reported AGK mutation-positive Sengers patients, confirming that Sengers syndrome is a clinically recognisable disorder of mitochondrial energy metabolism (PMID:25208612)
• findings provide new evidence that AGK plays an important role in promoting angiogenesis and providing resistance to apoptosis in hepatocellular carcinoma (PMID:25474138)
• AGK promotes the proliferation and cell cycle progression of oral squamous cell carcinoma. (PMID:25872568)
• miR-194 could reduce the phosphoinositide 3-kinase (PI3K)/AKT/FoxO3a signaling pathway by suppressing acylglycerol kinase (AGK) directly. (PMID:25960215)
• Data suggest that acylglycerol kinase (AGK) has potential as a prognostic factor for overall survival in nasopharyngeal carcinoma (NPC). (PMID:26443540)
• We showed that AGK was over-expressed in cervical cancer cell lines and clinical tissues, and over-expression of AGK was associated with poor survival outcomes of early-stage CSCC patients. AGK can be used as an independent prognostic marker for early-stage CSCC. (PMID:26662108)
• Acylglycerol kinase functions as an oncogene and an unfavorable prognostic marker for human gliomas. (PMID:27574811)
• The dual function of AGK as lipid kinase and constituent of the TIM22 complex reveals that disturbances in both phospholipid metabolism and mitochondrial protein biogenesis contribute to the pathogenesis of Sengers syndrome. (PMID:28712724)
• Identify AGK as a bona fide subunit of TIM22 providing an exciting and unexpected link between mitochondrial protein import and Sengers syndrome. (PMID:28712726)
• miR-610 expression was significantly downregulated in both oral squamous cell carcinoma (OSCC) tissues and cell lines. Low miR-610 expression was associated with advanced T classification, TNM stage and poorer prognosis. Overexpression of miR-610 significantly suppressed OSCC cells proliferation, migration, invasion and EMT process. Mechanistically, AGK was confirmed to be the downstream target of miR-610 in OSCC cells. (PMID:30657560)
• Acylglycerol kinase promotes tumour growth and metastasis via activating the PI3K/AKT/GSK3beta signalling pathway in renal cell carcinoma. (PMID:31900208)
• The role of AGK in thrombocytopoiesis and possible therapeutic strategies. (PMID:32202634)
• Up-regulated acylglycerol kinase (AGK) expression associates with gastric cancer progression through the formation of a novel YAP1-AGK-positive loop. (PMID:32827244)
• Defining the architecture of the human TIM22 complex by chemical crosslinking. (PMID:33125709)
• Acylglycerol kinase promotes paclitaxel resistance in nasopharyngeal carcinoma cells by regulating FOXM1 via the JAK2/STAT3 pathway. (PMID:34116927)
• Downregulation of acylglycerol kinase suppresses high-glucose-induced endothelial-mesenchymal transition in human retinal microvascular endothelial cells through regulating the LPAR1/TGF-beta/Notch signaling pathway. (PMID:34559978)
• Excellent Response to MEK Inhibition in an AGK-BRAF Gene Fusion Driven Carcinoma: Case Report and Literature Review. (PMID:34969747)
• Circ_0008068 facilitates the oral squamous cell carcinoma development by microRNA-153-3p/acylgycerol kinase (AGK) axis. (PMID:35635053)
• Acylglycerol kinase promotes ovarian cancer progression and regulates mitochondria function by interacting with ribosomal protein L39. (PMID:35934718)
• Sengers syndrome and AGK-related disorders - Minireview of phenotypic variability and clinical outcomes in molecularly confirmed cases. (PMID:37354892)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	agk	ENSDARG00000009837
mus_musculus	Agk	ENSMUSG00000029916
rattus_norvegicus	Agk	ENSRNOG00000011509
drosophila_melanogaster	Mulk	FBGN0260750
caenorhabditis_elegans		WBGENE00018674

Paralogs (4): SPHK2 (ENSG00000063176), CERK (ENSG00000100422), SPHK1 (ENSG00000176170), CERKL (ENSG00000188452)

Protein

Protein identifiers

Acylglycerol kinase, mitochondrial — Q53H12 (reviewed: Q53H12)

Alternative names: Multiple substrate lipid kinase

All UniProt accessions (13): Q53H12, A0A3B3IRM6, A0A3B3IS09, A0A3B3ISY9, A0A3B3ISZ0, A0A3B3ITD0, A0A3B3ITV0, A0A3B3ITX7, A0A3B3IUC9, A4D1U5, E9PC15, E9PG39, F8WDD1

UniProt curated annotations — full annotation on UniProt →

Function. Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively. Does not phosphorylate sphingosine. Phosphorylates ceramide. Phosphorylates 1,2-dioleoylglycerol more rapidly than 2,3-dioleoylglycerol. Independently of its lipid kinase activity, acts as a component of the TIM22 complex. The TIM22 complex mediates the import and insertion of multi-pass transmembrane proteins into the mitochondrial inner membrane by forming a twin-pore translocase that uses the membrane potential as the external driving force. In the TIM22 complex, required for the import of a subset of metabolite carriers into mitochondria, such as ANT1/SLC25A4 and SLC25A24, while it is not required for the import of TIMM23. Overexpression increases the formation and secretion of LPA, resulting in transactivation of EGFR and activation of the downstream MAPK signaling pathway, leading to increased cell growth.

Subunit / interactions. Component of the TIM22 complex, which core is composed of TIMM22, associated with TIMM10 (TIMM10A and/or TIMM10B), TIMM9, AGK and TIMM29. Interacts with SMIM26.

Subcellular location. Mitochondrion inner membrane. Mitochondrion intermembrane space.

Tissue specificity. Highly expressed in muscle, heart, kidney and brain.

Disease relevance. Mitochondrial DNA depletion syndrome 10 (MTDPS10) [MIM:212350] An autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy. The disease is caused by variants affecting the gene represented in this entry. The TIM22 complex and import of proteins into mitochondrion are affected in patients suffering of MTDPS10. Cataract 38 (CTRCT38) [MIM:614691] An opacification of the crystalline lens of the eye becoming evident at birth. It frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. The disease is caused by variants affecting the gene represented in this entry.

Induction. Overexpressed in prostate cancer, suggesting that it may play a role in initiation and progression of prostate cancer, processes in which lysophosphatidic acid (LPA) plays key roles.

Pathway. Lipid metabolism; glycerolipid metabolism.

Similarity. Belongs to the AGK family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q53H12-1	1	yes
Q53H12-2	2

RefSeq proteins (2): NP_001351877, NP_060708* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001206	Diacylglycerol_kinase_cat_dom	Domain
IPR016064	NAD/diacylglycerol_kinase_sf	Homologous_superfamily
IPR017438	ATP-NAD_kinase_N	Homologous_superfamily
IPR045579	AGK_C	Domain
IPR050187	Lipid_Phosphate_FormReg	Family

Pfam: PF00781, PF19712

Enzyme classification (BRENDA):

• EC 2.7.1.94 — acylglycerol kinase (BRENDA: 8 organisms, 48 substrates, 8 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 11 shown:

• a 1,2-diacyl-sn-glycerol + ATP = a 1,2-diacyl-sn-glycero-3-phosphate + ADP + H(+) (RHEA:10272)
• an N-acylsphing-4-enine + ATP = an N-acylsphing-4-enine 1-phosphate + ADP + H(+) (RHEA:17929)
• a monoacylglycerol + ATP = a monoacyl-sn-glycero-3-phosphate + ADP + H(+) (RHEA:19293)
• a 1-acyl-sn-glycerol + ATP = a 1-acyl-sn-glycero-3-phosphate + ADP + H(+) (RHEA:33747)
• a 2-acylglycerol + ATP = a 2-acyl-sn-glycerol 3-phosphate + ADP + H(+) (RHEA:39847)
• 1,2-di-(9Z-octadecenoyl)-sn-glycerol + ATP = 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40327)
• 1-(9Z-octadecenoyl)-sn-glycerol + ATP = 1-(9Z-octadecenoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:41079)
• 1-hexadecanoyl-sn-glycerol + ATP = 1-hexadecanoyl-sn-glycero-3-phosphate + ADP + H(+) (RHEA:43308)
• N-(hexanoyl)sphing-4-enine + ATP = N-hexanoylsphing-4-enine 1-phosphate + ADP + H(+) (RHEA:43312)
• 2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol + ATP = 2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:43316)
• 1-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycerol + ATP = 1-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:43328)

UniProt features (13 total): sequence variant 4, region of interest 2, splice variant 2, chain 1, domain 1, mutagenesis site 1, sequence conflict 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7CGP	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53H12-F1	86.93	0.57

Functional residue map

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

Post-translational modifications (1): 6

Mutagenesis-validated functional residues (1):

Position	Phenotype
126	abolishes lipid kinase activity. does not affect ability to associate with the tim22 complex and mediate import of trans

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-1483206	Glycerophospholipid biosynthesis
R-HSA-6802952	Signaling by BRAF and RAF1 fusions
R-HSA-1430728	Metabolism
R-HSA-1483257	Phospholipid metabolism
R-HSA-1643685	Disease
R-HSA-556833	Metabolism of lipids
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-6802957	Oncogenic MAPK signaling

MSigDB gene sets: 264 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GGGACCA_MIR133A_MIR133B, GOBP_LIPID_MODIFICATION, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_POLYOL_METABOLIC_PROCESS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, MARTINEZ_RB1_TARGETS_UP, GOBP_SPHINGOID_METABOLIC_PROCESS, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_INNER_MITOCHONDRIAL_MEMBRANE_ORGANIZATION, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_AMIDE_BIOSYNTHETIC_PROCESS

GO Biological Process (6): protein insertion into mitochondrial inner membrane (GO:0045039), glycerolipid metabolic process (GO:0046486), sphingosine biosynthetic process (GO:0046512), ceramide biosynthetic process (GO:0046513), lipid phosphorylation (GO:0046834), lipid metabolic process (GO:0006629)

GO Molecular Function (11): ceramide kinase activity (GO:0001729), ATP-dependent diacylglycerol kinase activity (GO:0004143), ATP binding (GO:0005524), acylglycerol kinase activity (GO:0047620), nucleotide binding (GO:0000166), lipid kinase activity (GO:0001727), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), phosphotransferase activity, alcohol group as acceptor (GO:0016773), obsolete D-erythro-sphingosine kinase activity (GO:0017050)

GO Cellular Component (9): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial inner membrane (GO:0005743), mitochondrial intermembrane space (GO:0005758), cytosol (GO:0005829), membrane (GO:0016020), mitochondrial membrane (GO:0031966), TIM22 mitochondrial import inner membrane insertion complex (GO:0042721)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Phospholipid metabolism	1
Oncogenic MAPK signaling	1
Metabolism of lipids	1
Metabolism	1
Disease	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
lipid kinase activity	2
phosphotransferase activity, alcohol group as acceptor	2
kinase activity	2
transferase activity, transferring phosphorus-containing groups	2
cytoplasm	2
mitochondrial membrane	2
mitochondrial envelope	2
inner mitochondrial membrane organization	1
mitochondrial protein import pathway	1
lipid metabolic process	1
sphingosine metabolic process	1
diol biosynthetic process	1
sphingoid biosynthetic process	1
ceramide metabolic process	1
sphingolipid biosynthetic process	1
phosphorylation	1
lipid modification	1
primary metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
organelle outer membrane	1
organelle inner membrane	1
organelle envelope lumen	1
mitochondrion	1
organelle membrane	1
inner mitochondrial membrane protein complex	1

Protein interactions and networks

STRING

2037 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AGK	TIMM29	Q9BSF4	801
AGK	TIMM10B	Q9Y5J6	781
AGK	TIMM22	Q9Y584	658
AGK	SERAC1	Q96JX3	618
AGK	TAMM41	Q96BW9	539
AGK	DNAJC19	Q96DA6	531
AGK	TIMM50	Q3ZCQ8	530
AGK	RENBP	P51606	528
AGK	DGUOK	P78532	520
AGK	EGFR	P00533	508
AGK	SUCLA2	Q9P2R7	502
AGK	SLC25A4	P12235	487
AGK	MGME1	Q9BQP7	486
AGK	SUCLG1	P53597	483
AGK	FBXL4	Q9UKA2	475

IntAct

119 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
SMIM26	AGK	psi-mi:“MI:0915”(physical association)	0.650
SMIM26	AGK	psi-mi:“MI:0403”(colocalization)	0.650
AGK	SMIM26	psi-mi:“MI:0403”(colocalization)	0.650
AGK	SMIM26	psi-mi:“MI:0914”(association)	0.650
SMIM26	AGK	psi-mi:“MI:0914”(association)	0.650
TIMM10	AGK	psi-mi:“MI:0914”(association)	0.640
SMIM26	SLC25A11	psi-mi:“MI:0914”(association)	0.630
HCCS	AGK	psi-mi:“MI:0915”(physical association)	0.620
AGK	HCCS	psi-mi:“MI:0914”(association)	0.620
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
HTT	AGK	psi-mi:“MI:0915”(physical association)	0.560
AP3S1	AP3B1	psi-mi:“MI:0914”(association)	0.530
RSPRY1	NEFL	psi-mi:“MI:0914”(association)	0.530

BioGRID (185): AGK (Affinity Capture-MS), AGK (Affinity Capture-MS), AGK (Affinity Capture-MS), AGK (Affinity Capture-MS), AGK (Affinity Capture-MS), AGK (Proximity Label-MS), AGK (Proximity Label-MS), AGK (Proximity Label-MS), AGK (Proximity Label-MS), AGK (Proximity Label-MS), AGK (Affinity Capture-MS), AGK (Affinity Capture-MS), AGK (Affinity Capture-MS), AGK (Affinity Capture-MS), TIMM10B (Affinity Capture-MS)

ESM2 similar proteins: A4FUF0, A6NNS2, A9UM79, D3ZGP9, G3X9X1, O54929, O94955, O95825, P10868, P14893, P26149, P27365, P42694, Q0P5D8, Q0V8J1, Q1RMJ5, Q3UFS0, Q49A26, Q4R7G8, Q53H12, Q562D5, Q59A28, Q5IFP1, Q5R7T2, Q5RAF1, Q5RED7, Q5RJL2, Q5RKH0, Q5RKN4, Q5ZLS7, Q62878, Q6DFV5, Q6PC62, Q86XA0, Q8CA95, Q8CHS7, Q8IX04, Q8N475, Q8VCM5, Q8VHQ9

Diamond homologs: A4WCD7, A5IU64, A6QIC6, A6U302, A7MHI5, A7X424, A8GHR8, A8Z2R1, B5XPB3, B9DMT6, F2Y4A3, O31502, Q1QUK4, Q2FFJ7, Q2FWZ2, Q2NYP7, Q2YU29, Q3BYC8, Q49YU2, Q4L7L1, Q53H12, Q5GVG9, Q5HEM4, Q5HN36, Q5RED7, Q6G835, Q6GFF9, Q7A0H3, Q7A4Q8, Q7ZYJ3, Q87IB3, Q8CRU5, Q8PQ53, Q97QZ6, Q99SY8, Q9ESW4, A1ACV5, A1JKV8, A4TMR9, A7FG10

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AGK	“form complex”	“TIM22 complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	40
Likely pathogenic	14
Uncertain significance	148
Likely benign	150
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1033892	NM_018238.4(AGK):c.1039_1042dup (p.Ile348fs)	Pathogenic
1070308	NM_018238.4(AGK):c.1035dup (p.Ile346fs)	Pathogenic
1351396	NM_018238.4(AGK):c.412C>T (p.Arg138Ter)	Pathogenic
1415657	NM_018238.4(AGK):c.632G>A (p.Trp211Ter)	Pathogenic
1456624	NC_000007.13:g.(?141255267)(141301100_?)del	Pathogenic
1700787	NM_018238.4(AGK):c.979A>T (p.Lys327Ter)	Pathogenic
1705023	NM_018238.4(AGK):c.518+1G>A	Pathogenic
2021455	NM_018238.4(AGK):c.1166_1167dup (p.Tyr390fs)	Pathogenic
209130	NM_018238.4(AGK):c.409C>T (p.Arg137Ter)	Pathogenic
2120043	NM_018238.4(AGK):c.860G>A (p.Trp287Ter)	Pathogenic
214076	NM_018238.4(AGK):c.3G>C (p.Met1Ile)	Pathogenic
2426458	NC_000007.13:g.(?141292926)(141293005_?)del	Pathogenic
2580922	NM_018238.4(AGK):c.628C>T (p.Arg210Ter)	Pathogenic
280668	NM_018238.4(AGK):c.102-1G>T	Pathogenic
2921399	NM_018238.4(AGK):c.356dup (p.Ile120fs)	Pathogenic
2931348	NM_018238.4(AGK):c.25C>T (p.Arg9Ter)	Pathogenic
2947480	NM_018238.4(AGK):c.388G>T (p.Glu130Ter)	Pathogenic
2952828	NM_018238.4(AGK):c.409del (p.Arg137fs)	Pathogenic
3024642	GRCh37/hg19 7q34(chr7:140426294-141883173)x1	Pathogenic
30823	NM_018238.4(AGK):c.141+2T>C	Pathogenic
30824	NM_018238.4(AGK):c.1170T>G (p.Tyr390Ter)	Pathogenic
30825	NM_018238.4(AGK):c.975+1G>T	Pathogenic
30827	NM_018238.4(AGK):c.517C>T (p.Gln173Ter)	Pathogenic
30828	NM_018238.4(AGK):c.306T>G (p.Tyr102Ter)	Pathogenic
30829	NM_018238.4(AGK):c.841C>T (p.Arg281Ter)	Pathogenic
30830	NM_018238.4(AGK):c.672C>G (p.Tyr224Ter)	Pathogenic
30831	NM_018238.4(AGK):c.1131+5G>A	Pathogenic
3245750	NC_000007.13:g.(?140434397)(141759786_?)del	Pathogenic
3245751	NC_000007.13:g.(?141351305)(141352724_?)del	Pathogenic
3381949	NM_018238.4(AGK):c.871C>T (p.Gln291Ter)	Pathogenic

SpliceAI

3074 predictions. Top by Δscore:

Variant	Effect	Δscore
7:141551430:CCGTG:C	donor_gain	1.0000
7:141551432:GTG:G	donor_gain	1.0000
7:141551433:TG:T	donor_gain	1.0000
7:141551434:GG:G	donor_gain	1.0000
7:141551435:G:GG	donor_gain	1.0000
7:141596556:TTTTA:T	acceptor_loss	1.0000
7:141596557:TTTA:T	acceptor_loss	1.0000
7:141596558:TTA:T	acceptor_loss	1.0000
7:141596559:TAGGT:T	acceptor_loss	1.0000
7:141596560:A:AG	acceptor_gain	1.0000
7:141596561:G:GG	acceptor_gain	1.0000
7:141596561:GGT:G	acceptor_gain	1.0000
7:141601203:A:AG	acceptor_gain	1.0000
7:141601204:G:GA	acceptor_gain	1.0000
7:141601204:GA:G	acceptor_gain	1.0000
7:141601204:GAA:G	acceptor_gain	1.0000
7:141601204:GAAA:G	acceptor_gain	1.0000
7:141601204:GAAAA:G	acceptor_gain	1.0000
7:141601276:TTAAG:T	donor_loss	1.0000
7:141601277:TAAGG:T	donor_loss	1.0000
7:141601278:AAGG:A	donor_loss	1.0000
7:141601279:AGGT:A	donor_loss	1.0000
7:141601280:GG:G	donor_loss	1.0000
7:141601281:G:C	donor_loss	1.0000
7:141601282:T:A	donor_loss	1.0000
7:141611193:A:AG	acceptor_gain	1.0000
7:141611194:G:GA	acceptor_gain	1.0000
7:141611194:GACA:G	acceptor_gain	1.0000
7:141611284:GGAG:G	donor_gain	1.0000
7:141611285:G:GT	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000007402 (7:141585286 G>A), RS1000038583 (7:141585003 T>A), RS1000062414 (7:141617625 A>G,T), RS1000084200 (7:141635441 A>C), RS1000139433 (7:141564816 G>T), RS1000186258 (7:141566747 C>T), RS1000188305 (7:141562267 G>A), RS1000196664 (7:141652225 T>C), RS1000216213 (7:141609977 T>C,G), RS1000254964 (7:141578586 A>T), RS1000290284 (7:141551568 G>A), RS1000290541 (7:141607420 A>G), RS1000309866 (7:141652441 C>T), RS1000316323 (7:141558761 C>T), RS1000369905 (7:141600518 G>A,T)

Disease associations

OMIM: gene MIM:610345 | disease phenotypes: MIM:212350, MIM:614691, MIM:222470, MIM:143890

GenCC curated gene-disease

Disease	Classification	Inheritance
Sengers syndrome	Definitive	Autosomal recessive
total early-onset cataract	Supportive	Autosomal dominant
cataract 38	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (6): Sengers syndrome (MONDO:0008922), cataract 38 (MONDO:0013859), trichohepatoenteric syndrome 1 (MONDO:0024541), mitochondrial disease (MONDO:0044970), hypercholesterolemia, familial, 1 (MONDO:0007750), total early-onset cataract (MONDO:0021548)

Orphanet (5): Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome (Orphanet:1369), Early onset non-syndromic cataract (Orphanet:91492), Trichohepatoenteric syndrome (Orphanet:84064), Mitochondrial disease (Orphanet:68380), Homozygous familial hypercholesterolemia (Orphanet:391665)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000545	Myopia
HP:0000639	Nystagmus
HP:0000938	Osteopenia
HP:0001131	Corneal dystrophy
HP:0001252	Hypotonia
HP:0001268	Mental deterioration
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0001510	Growth delay
HP:0001639	Hypertrophic cardiomyopathy
HP:0001645	Sudden cardiac death
HP:0001695	Cardiac arrest
HP:0001873	Thrombocytopenia
HP:0002092	Pulmonary arterial hypertension
HP:0002093	Respiratory insufficiency
HP:0002151	Increased circulating lactate concentration
HP:0003128	Lactic acidosis
HP:0003198	Myopathy
HP:0003324	Generalized muscle weakness
HP:0003388	Easy fatigability
HP:0003535	3-Methylglutaconic aciduria
HP:0003546	Exercise intolerance
HP:0003577	Congenital onset

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002862_1	Mood disorder and prion disease	2.000000e-06
GCST011109_4	Psoriasis	2.000000e-15

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538280	Cataract and cardiomyopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2417354 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.16	Kd	6966	nM	CHEMBL5653589
5.16	ED50	6966	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 31 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147816: Binding affinity to human AGK incubated for 45 mins by Kinobead based pull down assay	kd	6.9659	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression, decreases methylation	3
Benzo(a)pyrene	affects methylation	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	increases methylation	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
Bortezomib	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	increases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	decreases methylation	1
Doxorubicin	decreases expression	1
Hydralazine	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Methapyrilene	increases methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Testosterone	decreases expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1
tert-Butylhydroperoxide	decreases expression	1

ChEMBL screening assays

19 unique, capped per target: 19 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2422453	Binding	Inhibition of AGK in human PC3 cell lysates at 10 uM using desthiobiotin-tagged ATP probe AX9989 followed by trypsinization by LC/MS analysis	Hit-to-lead optimization and kinase selectivity of imidazo[1,2-a]quinoxalin-4-amine derived JNK1 inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1PQ	HAP1 AGK (-) 1	Cancer cell line	Male
CVCL_E1PR	HAP1 AGK (-) 2	Cancer cell line	Male
CVCL_E1PS	HAP1 AGK (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT06231459	PHASE4	COMPLETED	Expression of Pro- and Anti-inflammatory Cytokines During Anti-PCSK9 in Familial Hypercholesterolemia
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT00000594	PHASE3	COMPLETED	NHLBI Type II Coronary Intervention Study
NCT00092833	PHASE3	TERMINATED	Investigational Drug in Patients With Hypercholesterolemia or in Patients With Sitosterolemia (0653-026)(COMPLETED)
NCT00134485	PHASE3	COMPLETED	Study To Evaluate The Safety And Efficacy Of Torcetrapib/Atorvastatin In Subjects With Familial Hypercholerolemia
NCT00134511	PHASE3	COMPLETED	Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Patients With Genetic High Cholesterol Disorder
NCT00136981	PHASE3	COMPLETED	Carotid B-Mode Ultrasound Study to Compare Anti-Atherosclerotic Effect of Torcetrpib/Atorvastatin to Atorvastatin Alone.
NCT00384293	PHASE3	TERMINATED	Carotid IMT (Intima Media Thickening) Study (0524A-041)(TERMINATED)
NCT01524289	PHASE3	COMPLETED	Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020)
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00280995	PHASE2	COMPLETED	Dose-escalating Safety Study of ISIS 301012 in Homozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT00281008	PHASE2	COMPLETED	Study of ISIS 301012 (Mipomersen) in Heterozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT01375751	PHASE2	COMPLETED	Reduction of Low-Density Lipoprotein Cholesterol (LDL-C) With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement