GARS1

Summary

GARS1 (glycyl-tRNA synthetase 1, HGNC:4162) is a protein-coding gene on chromosome 7p14.3, encoding Glycine–tRNA ligase (P41250). Catalyzes the ATP-dependent ligation of glycine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP). It is a common-essential gene (DepMap: required in 98.8% of cancer cell lines).

This gene encodes glycyl-tRNA synthetase, one of the aminoacyl-tRNA synthetases that charge tRNAs with their cognate amino acids. The encoded enzyme is an (alpha)2 dimer which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2617 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease type 2D (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 904 total — 14 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 42
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 98.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_002047

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4162
Approved symbol	GARS1
Name	glycyl-tRNA synthetase 1
Location	7p14.3
Locus type	gene with protein product
Status	Approved
Aliases	GlyRS, DSMAV, SMAD1
Ensembl gene	ENSG00000106105
Ensembl biotype	protein_coding
OMIM	600287
Entrez	2617

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 13 nonsense_mediated_decay, 12 protein_coding, 12 retained_intron

ENST00000389266, ENST00000444666, ENST00000454308, ENST00000465748, ENST00000470392, ENST00000478124, ENST00000484093, ENST00000485784, ENST00000496643, ENST00000674616, ENST00000674643, ENST00000674734, ENST00000674737, ENST00000674807, ENST00000674815, ENST00000674851, ENST00000674969, ENST00000675025, ENST00000675051, ENST00000675529, ENST00000675587, ENST00000675651, ENST00000675693, ENST00000675810, ENST00000675859, ENST00000675863, ENST00000675886, ENST00000676088, ENST00000676140, ENST00000676164, ENST00000676210, ENST00000676259, ENST00000676403, ENST00000867346, ENST00000867347, ENST00000924894, ENST00000954857

RefSeq mRNA: 2 — MANE Select: NM_002047 NM_001316772, NM_002047

CCDS: CCDS43564

Canonical transcript exons

ENST00000389266 — 17 exons

Exon	Start	End
ENSE00000832199	30594878	30595143
ENSE00001505311	30622317	30622462
ENSE00003478101	30626234	30626319
ENSE00003489665	30632247	30632437
ENSE00003506223	30617114	30617278
ENSE00003506788	30628560	30628669
ENSE00003530033	30612096	30612245
ENSE00003531150	30615896	30616058
ENSE00003581495	30598796	30598897
ENSE00003593708	30631448	30631541
ENSE00003596334	30633735	30634033
ENSE00003598364	30603034	30603122
ENSE00003606610	30621393	30621500
ENSE00003642592	30609585	30609730
ENSE00003655042	30599947	30600049
ENSE00003656325	30603496	30603572
ENSE00003680795	30601059	30601200

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 193.1215 / max 1661.9847, expressed in 1828 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
77992	193.1215	1828

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.66	gold quality
cartilage tissue	UBERON:0002418	98.70	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.65	gold quality
middle temporal gyrus	UBERON:0002771	98.15	gold quality
tibia	UBERON:0000979	98.08	gold quality
dorsal root ganglion	UBERON:0000044	97.93	gold quality
esophagus squamous epithelium	UBERON:0006920	97.86	gold quality
oocyte	CL:0000023	97.83	gold quality
substantia nigra pars compacta	UBERON:0001965	97.75	gold quality
stromal cell of endometrium	CL:0002255	97.64	gold quality
islet of Langerhans	UBERON:0000006	97.51	gold quality
pharyngeal mucosa	UBERON:0000355	97.44	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.40	gold quality
pons	UBERON:0000988	97.36	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.08	gold quality
parotid gland	UBERON:0001831	97.03	gold quality
cortical plate	UBERON:0005343	96.99	gold quality
pericardium	UBERON:0002407	96.85	gold quality
epithelium of esophagus	UBERON:0001976	96.76	gold quality
squamous epithelium	UBERON:0006914	96.76	gold quality
penis	UBERON:0000989	96.62	gold quality
mammalian vulva	UBERON:0000997	96.56	gold quality
pylorus	UBERON:0001166	96.56	gold quality
oral cavity	UBERON:0000167	96.40	gold quality
lateral globus pallidus	UBERON:0002476	96.39	gold quality
tongue squamous epithelium	UBERON:0006919	96.37	gold quality
ganglionic eminence	UBERON:0004023	96.29	gold quality
ventricular zone	UBERON:0003053	96.23	gold quality
gingiva	UBERON:0001828	96.22	gold quality
smooth muscle tissue	UBERON:0001135	96.13	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

33 targeting GARS1, 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-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-4796-3P	99.08	68.38	1681
HSA-MIR-181A-2-3P	98.91	67.60	1168
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-676-5P	98.49	68.87	1492
HSA-MIR-4252	98.45	66.37	987
HSA-MIR-3138	98.41	67.53	744
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-203B-5P	97.24	68.54	543
HSA-MIR-6718-5P	97.24	68.15	553

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Four disease-associated missense mutations in the glycyl tRNA synthetase gene in families with Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V (PMID:12690580)
• A novel heterozygous missense GARS gene mutation (D500N) was identified in members of a family affected byCharcot-Marie-Tooth type 2D. (PMID:16534118)
• We screened 100 patients with inherited and sporadic lower motor neuron degeneration and identified three novel missense mutations in the glycyl-tRNA synthetase (GARS) gene. (PMID:17101916)
• The crystal belonged to space group P4(3)2(1)2 or its enantiomorphic space group P4(1)2(1)2, & diffracted X-rays to 3.0 A resolution. The asymmetric unit contained 1 GlyRS molecule & had a solvent content of 69%. (PMID:17142907)
• Crystal structure of human wildtype and S581L-mutant glycyl-tRNA synthetase. (PMID:17544401)
• The structure of wild type and Charcot-Marie-Tooth-causing mutant of homodimeric GlyRS are reported. (PMID:17545306)
• Charcot-Marie-Tooth (CMT) disease-causing mutations of glycine-tRNA synthetase share a common defect in localization which may be connected to a change in surfaces at the dimer interface, and may cause a dominant axonal form of CMT (type 2D). (PMID:17595294)
• we present a comparison between the crystal structures of the eubacterial Escherichia coli and the human tRNA(Gly) acceptor stem microhelices and their surrounding hydration patterns. (PMID:18275849)
• GARS mutation is a rare cause of Charcot-Marie-Tooth neuropathy among Japanese patients. (PMID:19329989)
• No pathogenic mutations were found, excluding the role of GARS gene as a possible factor in the aetiology of Hirayama disease in this cohort (PMID:19412816)
• human glycyl-tRNA synthetase has a role in Ap4A homeostasis (PMID:19710017)
• missense mutations of Gars may cause some loss of function, the dominant neuropathy phenotype observed in mice is caused by a dose-dependent gain of function that is not mitigated by over-expression of functional wild-type protein. (PMID:22144914)
• GRS bound to different ERK-activated tumor cells, and released phosphatase 2A (PP2A) from CDH6. (PMID:22345558)
• we believe that these two novel GARS mutations are the underlying causes of the distal hereditary motor neuropathy type V phenotype (PMID:23279345)
• We developed an ELISA to detect anti-glycyl-tRNA synthetase by using recombinant protein (PMID:24508626)
• This study presents genetic evidence for common mutant-specific interactions between two CMT-associated aminoacyl-tRNA synthetases, lending support for a shared mechanism responsible for the synthetase-induced peripheral neuropathies. (PMID:24807208)
• Report crystal structures of wild type and mutant GlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. (PMID:24898252)
• our data indicate that impaired function is a key component of GARS-mediated CMT disease and emphasize the need for careful genetic and functional evaluation before implicating a variant in disease onset. (PMID:25168514)
• we propose that the disease-causing L129P mutant of glycyl-tRNA synthetase is linked to a distribution defect in peripheral nerves in vivo. (PMID:25218976)
• Our findings suggest that mutant GlyRS gains access to ectopic sub-compartments of the motor neuron, providing a possible explanation for the selective neuropathology caused by mutations in a widely expressed gene. (PMID:25972375)
• The c.999G>T mutation is a novel mutation of the glycyl-tRNA synthetase gene that has not been previously reported. The phenotype of this family is Charcot-Marie-Tooth disease type 2D, which is first reported in Chinese population. (PMID:26000875)
• Expression of three CMT-mutant GARS proteins in Drosophila induces defects in motor performance and motor and sensory neuron morphology, and shortens lifespan. (PMID:26138142)
• GARS mutations are an uncommon cause of Charcot-Marie-Tooth Disease (CMT) in Taiwan. The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT. (PMID:26244500)
• one of the mRNAs isoforms tightly controls expression and localization of human GARS. (PMID:26327585)
• This study reports two crystal structures of human GlyRS variants, in the free form and in complex with tRNA(Gly) respectively, and reveal new aspects of the glycylation mechanism. (PMID:26797133)
• Data indicate that dimerization is required for the dominant neurotoxicity of disease-associated GARS mutations and provide a rapid, tractable model for studying newly identified GARS variants for a role in human disease. (PMID:27008886)
• At the active site, a glycyl-AMP molecule is synthesized and is waiting for the transfer of the glycyl moiety to occur. (PMID:27261259)
• GlyRS functions as a chaperone that critically supports neddylation. (PMID:27348078)
• In this Chinese Han population a novel Charcot-Marie-Tooth disease-associated gene mutations of GARS (c.794C>T) was discovered. (PMID:27862672)
• In support of GARS variant pathogenicity, our patient shows striking phenotypic overlap with other patients having ARS-related recessive diseases; this observation is consistent with the essential function of GARS in both cellular locations. In summary, our clinical, genetic, and functional analyses expand the phenotypic spectrum associated with GARS variants (PMID:28675565)
• we have demonstrated that CMT2D mice display a pathological phenotype restricted to the nervous system, and that GlyRS-mediated disruption of Nrp1/VEGF-A signalling appears to be permissive to capillary maturation and maintenance. (PMID:28835631)
• ignificant alterations of the vesicle-associated membrane protein-associated protein B (VAPB) and its downstream pathways such as mitochondrial calcium uptake and autophagy were detected in dominant GARS mutations. The role of VAPB has been supported by similar results in the GarsC210R mice. Our data suggest that altered mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) may be important disease mechanisms (PMID:29648643)
• A novel heterozygous missense mutation c.794C>A (p.Ser265Tyr) in the GARS gene associated with Charcot-Marie-Tooth disease in a Malian family. (PMID:31173493)
• Clinical and Genetic Features in a Series of Eight Unrelated Patients with Neuropathy Due to Glycyl-tRNA Synthetase (GARS) Variants. (PMID:31985473)
• GARS-related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment. (PMID:32181591)
• Associations between Neurological Diseases and Mutations in the Human Glycyl-tRNA Synthetase. (PMID:33827397)
• Charcot-Marie-Tooth mutation in glycyl-tRNA synthetase stalls ribosomes in a pre-accommodation state and activates integrated stress response. (PMID:34403468)
• GARS is implicated in poor survival and immune infiltration of hepatocellular carcinoma. (PMID:35271987)
• Pathogenic missense variants altering codon 336 of GARS1 lead to divergent dominant phenotypes. (PMID:35332613)
• Two distinct receptor-binding domains of human glycyl-tRNA synthetase 1 displayed on extracellular vesicles activate M1 polarization and phagocytic bridging of macrophages to cancer cells. (PMID:35523311)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gars1	ENSDARG00000059070
mus_musculus	Gars1	ENSMUSG00000029777
rattus_norvegicus	Gars1	ENSRNOG00000011052
drosophila_melanogaster	GlyRS	FBGN0027088
caenorhabditis_elegans		WBGENE00001744

Paralogs (1): POLG2 (ENSG00000256525)

Protein

Protein identifiers

Glycine–tRNA ligase — P41250 (reviewed: P41250)

Alternative names: Diadenosine tetraphosphate synthetase, Glycyl-tRNA synthetase, Glycyl-tRNA synthetase 1

All UniProt accessions (18): P41250, A0A6Q8PF45, A0A6Q8PFN0, A0A6Q8PFU7, A0A6Q8PFV5, A0A6Q8PFZ6, A0A6Q8PGA8, A0A6Q8PGI6, A0A6Q8PGN7, A0A6Q8PGT3, A0A6Q8PGW4, A0A6Q8PGZ8, A0A6Q8PGZ9, A0A6Q8PH49, A0A6Q8PHH9, A0A6Q8PHI7, F8WCK4, H7C443

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the ATP-dependent ligation of glycine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP). Also produces diadenosine tetraphosphate (Ap4A), a universal pleiotropic signaling molecule needed for cell regulation pathways, by direct condensation of 2 ATPs. Thereby, may play a special role in Ap4A homeostasis.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Cell projection. Axon. Secreted. Extracellular exosome Mitochondrion. Cytoplasm Cytoplasm.

Tissue specificity. Widely expressed, including in brain and spinal cord. Expressed in brain, spinal cord, muscle, heart and spleen. Expressed in brain, spinal cord, muscle, heart, spleen and liver.

Disease relevance. Charcot-Marie-Tooth disease, axonal, type 2D (CMT2D) [MIM:601472] A dominant axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. The disease is caused by variants affecting the gene represented in this entry. Neuronopathy, distal hereditary motor, autosomal dominant 5 (HMND5) [MIM:600794] A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. The disease is caused by variants affecting the gene represented in this entry. Spinal muscular atrophy, infantile, James type (SMAJI) [MIM:619042] An autosomal dominant form of spinal muscular atrophy, a group of neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMAJI is a severe disease characterized by hypotonia manifesting in the first weeks or months of life, delayed motor development, motor regression, and muscle weakness and atrophy primarily affecting distal muscles. Additional variable features include feeding difficulties, poor overall growth, foot deformities, kyphosis, hyperlordosis, scoliosis, vocal cord dysfunction, and respiratory insufficiency. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Ap4A synthesis is inhibited by tRNA, via the disruption of the second ATP-binding site by direct blocking and/or by tRNA-induced conformational change.

Miscellaneous. Human GlyRS uses direct ATP condensation to synthesize Ap4A, a unique amino acid-independent mechanism, in contrast to the classical amino acid-dependent mechanism for synthesis of Ap4A by a tRNA synthetase, that involves the generation of an enzyme-bound aminoacyl-AMP which is then attacked by ATP to form Ap4A. The isoform 2 translation is regulated by an Internal Ribosome Entry Site (IRES) and an upstream Open Reading Frame. Both are important in hindering the synthesis of the mitochondrial GARS and target the translation of the cytosolic enzyme to ER-bound ribosomes.

Similarity. Belongs to the class-II aminoacyl-tRNA synthetase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P41250-1	1	yes
P41250-2	2

RefSeq proteins (2): NP_001303701, NP_002038* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000738	WHEP-TRS_dom	Domain
IPR002314	aa-tRNA-synt_IIb	Domain
IPR002315	tRNA-synt_gly	Family
IPR004154	Anticodon-bd	Domain
IPR006195	aa-tRNA-synth_II	Domain
IPR009068	uS15_NS1_RNA-bd_sf	Homologous_superfamily
IPR027031	Gly-tRNA_synthase/POLG2	Family
IPR033731	GlyRS-like_core	Domain
IPR036621	Anticodon-bd_dom_sf	Homologous_superfamily
IPR045864	aa-tRNA-synth_II/BPL/LPL	Homologous_superfamily

Pfam: PF00458, PF00587, PF03129

Enzyme classification (BRENDA):

• EC 6.1.1.14 — glycine-tRNA ligase (BRENDA: 28 organisms, 50 substrates, 19 inhibitors, 52 Km, 7 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
TRNAGLY	0.0001–0.0033	15
ATP	0.013–0.37	10
GLY	0.0003–0.67	8
GLYCINE	0.13–0.145	5
TRNA1GLY	0.0026	1
TRNAGLY(C271-G2C71)	0.0091	1
TRNAGLY(C2G71-C2A71)	0.0018	1
TRNAGLY(G1C72-A1U72)	0.0045	1
TRNAGLY(G1C72-G1U72)	0.001	1
TRNAGLY(U73-A73)	0.0031	1
TRNAGLY(U73-C73)	0.0046	1
TRNAGLY(U73-G73)	0.0059	1
TRNA2GLY	—	0

Catalyzed reactions (Rhea), 2 shown:

• tRNA(Gly) + glycine + ATP = glycyl-tRNA(Gly) + AMP + diphosphate (RHEA:16013)
• 2 ATP + H(+) = P(1),P(4)-bis(5’-adenosyl) tetraphosphate + diphosphate (RHEA:34935)

UniProt features (130 total): strand 37, helix 31, sequence variant 24, turn 10, binding site 7, mutagenesis site 7, modified residue 6, sequence conflict 4, transit peptide 1, chain 1, splice variant 1, domain 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
2ZT5	X-RAY DIFFRACTION	2.5
2ZT7	X-RAY DIFFRACTION	2.7
4KQE	X-RAY DIFFRACTION	2.74
2Q5I	X-RAY DIFFRACTION	2.8
2PMF	X-RAY DIFFRACTION	2.85
4QEI	X-RAY DIFFRACTION	2.88
2PME	X-RAY DIFFRACTION	2.9
5E6M	X-RAY DIFFRACTION	2.93
2Q5H	X-RAY DIFFRACTION	3
2ZT6	X-RAY DIFFRACTION	3.08
4KR3	X-RAY DIFFRACTION	3.23
4KR2	X-RAY DIFFRACTION	3.29
2ZT8	X-RAY DIFFRACTION	3.35
2ZXF	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41250-F1	86.61	0.59

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 (7): 299; 331–333; 342–343; 350; 457–458; 576–578; 583

Post-translational modifications (6): 35, 204, 453, 501, 700, 736

Mutagenesis-validated functional residues (7):

Position	Phenotype
121	decrease in catalytic activity by about 10-fold.
211	displays 62% of wild-type catalytic activity. displays 20% of wild-type catalytic activity; when associated with g-125.
337	decrease in catalytic activity by more than 10-fold.
486–490	loss of catalytic activity.
602	decrease in catalytic activity by more than 10-fold.
658	decrease in catalytic activity by more than 10-fold.
729	decrease in catalytic activity by about 10-fold.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-379716	Cytosolic tRNA aminoacylation
R-HSA-379726	Mitochondrial tRNA aminoacylation

MSigDB gene sets: 838 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_DENDRITE_DEVELOPMENT, MORF_DNMT1, GOBP_HINDBRAIN_DEVELOPMENT, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_AMINO_ACID_ACTIVATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, PAX4_01, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_CARTILAGE_DEVELOPMENT, MORF_BUB1

GO Biological Process (5): tRNA aminoacylation for protein translation (GO:0006418), diadenosine tetraphosphate biosynthetic process (GO:0015966), mitochondrial glycyl-tRNA aminoacylation (GO:0070150), translation (GO:0006412), glycyl-tRNA aminoacylation (GO:0006426)

GO Molecular Function (12): bis(5’-nucleosyl)-tetraphosphatase (asymmetrical) activity (GO:0004081), glycine-tRNA ligase activity (GO:0004820), ATP binding (GO:0005524), identical protein binding (GO:0042802), protein dimerization activity (GO:0046983), ATP:ATP adenylyltransferase activity (GO:0141192), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), protein binding (GO:0005515), transferase activity (GO:0016740), hydrolase activity (GO:0016787), ligase activity (GO:0016874)

GO Cellular Component (9): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), secretory granule (GO:0030141), axon (GO:0030424), extracellular exosome (GO:0070062), extracellular region (GO:0005576), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
tRNA Aminoacylation	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
catalytic activity	3
mitochondrion	2
protein binding	2
cytoplasm	2
translation	1
tRNA aminoacylation	1
diadenosine polyphosphate biosynthetic process	1
glycyl-tRNA aminoacylation	1
tRNA aminoacylation for mitochondrial protein translation	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
tRNA aminoacylation for protein translation	1
bis(5’-nucleosyl)-tetraphosphatase activity	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
adenylyltransferase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ligase activity, forming carbon-oxygen bonds	1
catalytic activity, acting on a tRNA	1
binding	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
endomembrane system	1
secretory vesicle	1
neuron projection	1
extracellular vesicle	1

Protein interactions and networks

STRING

1981 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GARS1	HARS1	P12081	968
GARS1	YARS1	P54577	964
GARS1	GPHN	Q9NQX3	963
GARS1	HARS2	P49590	960
GARS1	AARS1	P49588	858
GARS1	YARS2	Q9Y2Z4	844
GARS1	KARS1	Q15046	843
GARS1	EPRS1	P07814	839
GARS1	IARS2	Q9NSE4	831
GARS1	TARS3	A2RTX5	826
GARS1	POLG2	Q9UHN1	824
GARS1	TARS2	Q9BW92	823
GARS1	TARS1	P26639	820
GARS1	MARS1	P56192	803
GARS1	IARS1	P41252	799

IntAct

118 interactions, top by confidence:

A	B	Type	Score
PSMC3	PSMD9	psi-mi:“MI:0914”(association)	0.940
HRAS	MTHFD2	psi-mi:“MI:0914”(association)	0.730
GARS1	GARS1	psi-mi:“MI:0407”(direct interaction)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PSMC3	PSMD12	psi-mi:“MI:0914”(association)	0.640
GARS1	Gars1	psi-mi:“MI:0915”(physical association)	0.590
KLF6	GARS1	psi-mi:“MI:0915”(physical association)	0.560
PCDHGC3	GARS1	psi-mi:“MI:0915”(physical association)	0.560
COPS3	GARS1	psi-mi:“MI:0915”(physical association)	0.560
BATF	GARS1	psi-mi:“MI:0915”(physical association)	0.560
SPAG8	GARS1	psi-mi:“MI:0915”(physical association)	0.560
SOCS4	GARS1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (327): GARS (Affinity Capture-MS), GARS (Two-hybrid), GARS (Affinity Capture-RNA), AGL (Co-fractionation), EPRS (Co-fractionation), GARS (Co-fractionation), GARS (Co-fractionation), GARS (Co-fractionation), GARS (Co-fractionation), GARS (Co-fractionation), GARS (Co-fractionation), GARS (Co-fractionation), GARS (Co-fractionation), GARS (Co-fractionation), GARS (Co-fractionation)

ESM2 similar proteins: A0AVT1, A2RTX5, A6QNM8, F4IFC5, O04630, O13914, O13969, O16129, O75879, P04801, P07236, P13642, P21894, P26636, P26638, P26639, P41250, P49588, P49591, P50475, P52709, P87144, Q0V9S0, Q3ZBV8, Q4R4U9, Q4R646, Q54J66, Q5R9K9, Q5RC02, Q5XHY5, Q5ZKA2, Q6DRC0, Q6P799, Q8BGQ7, Q8BGV0, Q8BIJ6, Q8BLY2, Q8CFX8, Q8GZ45, Q8H104

Diamond homologs: A0B5U4, A1TBP9, A3DF15, A4FZX1, A4ITQ8, A5IT93, A5N4L2, A6LPL6, A6QHA8, A6TSJ4, A6U237, A6URK3, A6VIK1, A7X2W2, A8MG73, A8Z4A4, A9A885, A9KJ36, B1AJD3, B1HTI6, B2S075, B2S3R1, B5ZC00, B7J1U3, B8I2Z6, B9DNL1, B9DY74, B9E6V6, B9L0I4, C4Z1I4, C4ZAV7, C5A1H0, C6A317, O23627, O27874, O29346, O51344, O59235, O83678, P38088

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
QRICH1	“up-regulates quantity by expression”	GARS1	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	GARS1	“transcriptional regulation”
GARS1	“down-regulates quantity”	tRNA(Gly)	“chemical modification”
GARS1	“down-regulates quantity”	glycine	“chemical modification”
GARS1	“down-regulates quantity”	ATP(4-)	“chemical modification”
GARS1	“up-regulates quantity”	diphosphate(3-)	“chemical modification”
GARS1	“up-regulates quantity”	AMP	“chemical modification”
GARS1	“up-regulates quantity”	Gly-tRNA(Gly)	“chemical modification”
GARS1	“up-regulates quantity”	alpha-aminoacyl-tRNA	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 113 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
Defective CFTR causes cystic fibrosis	5	13.2×	3e-03
MyD88 cascade initiated on plasma membrane	5	12.3×	3e-03
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	5	11.5×	3e-03
MyD88 dependent cascade initiated on endosome	5	11.5×	3e-03
FCERI mediated NF-kB activation	6	11.3×	3e-03
CLEC7A (Dectin-1) signaling	6	10.3×	3e-03
Apoptosis	5	10.1×	5e-03
Activation of STAT3 by cadherin engagement	5	9.8×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
JNK cascade	6	16.1×	1e-03
DNA damage response	11	5.8×	1e-03
cilium assembly	8	5.8×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	10
Uncertain significance	459
Likely benign	246
Benign	57

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1342184	NM_002047.4(GARS1):c.1007C>A (p.Pro336His)	Pathogenic
1800098	NM_002047.4(GARS1):c.1462G>T (p.Glu488Ter)	Pathogenic
208650	NM_002047.4(GARS1):c.373G>A (p.Glu125Lys)	Pathogenic
2734981	NM_002047.4(GARS1):c.999G>C (p.Glu333Asp)	Pathogenic
410314	NM_002047.4(GARS1):c.1415A>G (p.His472Arg)	Pathogenic
431180	NM_002047.4(GARS1):c.246_249del (p.Glu83fs)	Pathogenic
476747	NM_002047.4(GARS1):c.1000A>T (p.Ile334Phe)	Pathogenic
476764	NM_002047.4(GARS1):c.875T>G (p.Met292Arg)	Pathogenic
661670	NM_002047.4(GARS1):c.979G>A (p.Gly327Arg)	Pathogenic
834274	NM_002047.4(GARS1):c.1001T>G (p.Ile334Ser)	Pathogenic
9205	NM_002047.4(GARS1):c.548T>C (p.Leu183Pro)	Pathogenic
9207	NM_002047.4(GARS1):c.1738G>C (p.Gly580Arg)	Pathogenic
981500	NM_002047.4(GARS1):c.1954G>C (p.Gly652Arg)	Pathogenic
984908	NM_002047.4(GARS1):c.794C>A (p.Ser265Tyr)	Pathogenic
1184913	NM_002047.4(GARS1):c.1415dup (p.His472fs)	Likely pathogenic
2115108	NM_002047.4(GARS1):c.1007C>T (p.Pro336Leu)	Likely pathogenic
216930	NM_002047.4(GARS1):c.998A>T (p.Glu333Val)	Likely pathogenic
3602190	NM_002047.4(GARS1):c.893C>G (p.Pro298Arg)	Likely pathogenic
4075475	NM_002047.4(GARS1):c.815T>G (p.Leu272Arg)	Likely pathogenic
410315	NM_002047.4(GARS1):c.1705G>A (p.Glu569Lys)	Likely pathogenic
421418	NM_002047.4(GARS1):c.875T>C (p.Met292Thr)	Likely pathogenic
423476	NM_002047.4(GARS1):c.998A>C (p.Glu333Ala)	Likely pathogenic
543246	NM_002047.4(GARS1):c.1034A>G (p.Glu345Gly)	Likely pathogenic
617635	NM_002047.4(GARS1):c.643G>C (p.Asp215His)	Likely pathogenic

SpliceAI

4465 predictions. Top by Δscore:

Variant	Effect	Δscore
4:145512093:T:TA	acceptor_gain	1.0000
4:145514434:GTA:G	acceptor_loss	1.0000
4:145514435:TA:T	acceptor_loss	1.0000
4:145514437:G:GC	acceptor_loss	1.0000
4:145542580:A:AG	acceptor_gain	1.0000
4:145542581:G:GG	acceptor_gain	1.0000
4:145542696:G:GT	donor_gain	1.0000
4:145546701:A:AG	acceptor_gain	1.0000
4:145546702:G:GA	acceptor_gain	1.0000
4:145546702:GA:G	acceptor_gain	1.0000
4:145546702:GAT:G	acceptor_gain	1.0000
4:145546920:AAAAG:A	donor_gain	1.0000
4:145546921:AAAG:A	donor_gain	1.0000
4:145546921:AAAGG:A	donor_loss	1.0000
4:145546922:AAG:A	donor_gain	1.0000
4:145546922:AAGG:A	donor_loss	1.0000
4:145546923:AG:A	donor_gain	1.0000
4:145546923:AGGT:A	donor_loss	1.0000
4:145546924:GG:G	donor_gain	1.0000
4:145546924:GGT:G	donor_loss	1.0000
4:145546925:G:C	donor_loss	1.0000
4:145546925:G:GG	donor_gain	1.0000
4:145553783:GGA:G	acceptor_gain	1.0000
7:30598789:T:A	acceptor_gain	1.0000
7:30598790:G:A	acceptor_gain	1.0000
7:30598790:GGCTA:G	acceptor_loss	1.0000
7:30598791:GCTA:G	acceptor_loss	1.0000
7:30598792:CTAG:C	acceptor_loss	1.0000
7:30598793:TA:T	acceptor_loss	1.0000
7:30598794:A:AG	acceptor_gain	1.0000

AlphaMissense

4862 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:30601067:G:C	G146R	1.000
7:30601068:G:A	G146D	1.000
7:30601083:G:A	G151E	1.000
7:30601092:G:A	G154D	1.000
7:30601124:T:A	W165R	1.000
7:30601124:T:C	W165R	1.000
7:30601171:C:G	C180W	1.000
7:30601194:T:A	V188D	1.000
7:30603039:C:T	S192F	1.000
7:30603044:C:G	H194D	1.000
7:30603046:T:A	H194Q	1.000
7:30603046:T:G	H194Q	1.000
7:30603056:T:C	F198L	1.000
7:30603057:T:C	F198S	1.000
7:30603057:T:G	F198C	1.000
7:30603058:T:A	F198L	1.000
7:30603058:T:G	F198L	1.000
7:30603101:C:A	R213S	1.000
7:30603101:C:G	R213G	1.000
7:30603114:T:C	L217P	1.000
7:30612104:G:C	R297T	1.000
7:30612105:A:C	R297S	1.000
7:30612105:A:T	R297S	1.000
7:30612107:C:A	P298Q	1.000
7:30612107:C:G	P298R	1.000
7:30612111:A:C	E299D	1.000
7:30612111:A:T	E299D	1.000
7:30612120:G:C	Q302H	1.000
7:30612120:G:T	Q302H	1.000
7:30612121:G:A	G303R	1.000

dbSNP variants (sampled 300 via entrez): RS1000023155 (7:30616788 T>C), RS1000066897 (7:30632933 G>A), RS1000112311 (7:30602047 A>G), RS1000168102 (7:30593360 AAAAG>A), RS1000372233 (7:30629981 C>A,T), RS1000376444 (7:30634044 A>G), RS1000458033 (7:30617127 A>G), RS1000613688 (7:30605393 A>G), RS1000720557 (7:30599307 T>A), RS1000745338 (7:30629725 A>C,G), RS1000799310 (7:30625310 G>A), RS1000850246 (7:30615292 A>G), RS1000900855 (7:30608438 T>C), RS1001001256 (7:30622208 A>T), RS1001044758 (7:30605092 T>G)

Disease associations

OMIM: gene MIM:600287 | disease phenotypes: MIM:601472, MIM:600794, MIM:118220, MIM:619042, MIM:182960, MIM:600361

GenCC curated gene-disease

Disease	Classification	Inheritance
neuronopathy, distal hereditary motor, type 5A	Definitive	Autosomal dominant
Charcot-Marie-Tooth disease type 2D	Strong	Autosomal dominant
spinal muscular atrophy, infantile, James type	Moderate	Autosomal dominant
mitochondrial disease	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease type 2D	Definitive	AD

Mondo (14): Charcot-Marie-Tooth disease type 2 (MONDO:0018993), Charcot-Marie-Tooth disease type 2D (MONDO:0011091), neuronopathy, distal hereditary motor, type 5A (MONDO:0015353), Charcot-Marie-Tooth disease (MONDO:0015626), distal hereditary motor neuropathy (MONDO:0018894), parkinsonian disorder (MONDO:0021095), Charcot-Marie-Tooth disease type 1 (MONDO:0019011), spinal muscular atrophy, infantile, James type (MONDO:0033621), neuronopathy, distal hereditary motor, type 5 (MONDO:0100350), motor neuron disorder (MONDO:0020128), hereditary motor neuron disease (MONDO:0024257), neuronopathy, distal hereditary motor, autosomal dominant (MONDO:0015362), Charcot-Marie-Tooth disease type 5 (MONDO:0010877), mitochondrial disease (MONDO:0044970)

Orphanet (10): Autosomal dominant Charcot-Marie-Tooth disease type 2 (Orphanet:64746), Autosomal dominant Charcot-Marie-Tooth disease type 2D (Orphanet:99938), Distal hereditary motor neuropathy type 5 (Orphanet:139536), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Distal hereditary motor neuropathy (Orphanet:53739), Charcot-Marie-Tooth disease type 1 (Orphanet:65753), Motor neuron disease (Orphanet:98503), Genetic motor neuron disease (Orphanet:98505), Autosomal dominant distal hereditary motor neuropathy (Orphanet:140465), Hereditary motor and sensory neuropathy type 5 (Orphanet:64751)

HPO phenotypes

42 total (30 of 42 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001621	Weak voice
HP:0001761	Pes cavus
HP:0001763	Pes planus
HP:0001765	Hammertoe
HP:0002093	Respiratory insufficiency
HP:0002172	Postural instability
HP:0002317	Unsteady gait
HP:0002460	Distal muscle weakness
HP:0002495	Impaired vibratory sensation
HP:0002650	Scoliosis
HP:0002936	Distal sensory impairment
HP:0002938	Lumbar hyperlordosis
HP:0003273	Hip contracture
HP:0003392	First dorsal interossei muscle weakness
HP:0003393	Thenar muscle atrophy
HP:0003426	First dorsal interossei muscle atrophy
HP:0003427	Thenar muscle weakness
HP:0003435	Cold-induced hand cramps
HP:0003484	Upper limb muscle weakness
HP:0003557	Increased variability in muscle fiber diameter
HP:0003593	Infantile onset
HP:0003677	Slowly progressive
HP:0003693	Distal amyotrophy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008839_561	Height	1.000000e-09

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D016472	Motor Neuron Disease	C10.574.562; C10.668.467
D020734	Parkinsonian Disorders	C10.228.140.079.862; C10.228.662.600
C537993	Charcot-Marie-Tooth disease, Type 2D (supp.)
C563443	Neuronopathy, Distal Hereditary Motor, Type V (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105815 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,167 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2105728	CRENOLANIB	3	2,167

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 5 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.43	Kd	37.38	nM	CHEMBL3752910
7.43	ED50	37.38	nM	CHEMBL3752910
7.40	Kd	40	nM	CRENOLANIB

PubChem BioAssay actives

2 with measured affinity, of 251 total; 2 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-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148417: Binding affinity to human GARS incubated for 45 mins by Kinobead based pull down assay	kd	0.0374	uM
1-[2-[5-[(3-methyloxetan-3-yl)methoxy]benzimidazol-1-yl]quinolin-8-yl]piperidin-4-amine	1425010: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0400	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	7
bisphenol A	increases expression, affects expression, decreases expression	4
sodium arsenite	increases expression, decreases expression	3
Acetaminophen	affects expression, affects cotreatment, increases expression	3
Benzo(a)pyrene	decreases expression, increases methylation	3
Estradiol	increases expression, affects cotreatment, decreases expression	3
Valproic Acid	increases expression, affects expression	3
Particulate Matter	increases abundance, increases expression, affects cotreatment, decreases expression	3
ochratoxin A	decreases expression, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Carbamazepine	affects expression	2
Cisplatin	increases expression, affects response to substance	2
Phenobarbital	affects expression, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
Tretinoin	decreases expression	2
Tunicamycin	increases expression	2
Aflatoxin B1	affects expression, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
Thapsigargin	increases expression	2
p-Chloromercuribenzoic Acid	increases expression, affects cotreatment	2
aristolochic acid I	increases expression, decreases expression	1
FR900359	increases phosphorylation	1
tremortin	increases expression	1
chloroacetaldehyde	affects expression	1
methylmercuric chloride	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctanoic acid	increases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991723	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

Cellosaurus cell lines

8 cell lines: 6 induced pluripotent stem cell, 1 telomerase immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C3K7	N/Tert-1 GARS	Telomerase immortalized cell line	Male
CVCL_F097	GM19903	Transformed cell line	Male
CVCL_RB68	STBCi018-A	Induced pluripotent stem cell	Male
CVCL_RB69	STBCi018-B	Induced pluripotent stem cell	Male
CVCL_RB70	STBCi018-C	Induced pluripotent stem cell	Male
CVCL_RC12	STBCi037-A	Induced pluripotent stem cell	Female
CVCL_RC13	STBCi037-B	Induced pluripotent stem cell	Female
CVCL_RC14	STBCi037-C	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

297 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
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
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
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT01951924	PHASE3	COMPLETED	LIME Study (LFB IVIg MMN Efficacy Study)
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
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
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
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