LARS2

Summary

LARS2 (leucyl-tRNA synthetase 2, mitochondrial, HGNC:17095) is a protein-coding gene on chromosome 3p21.31, encoding Leucine–tRNA ligase, mitochondrial (Q15031). Catalyzes the attachment of leucine to its cognate tRNA. It is a selective cancer dependency (DepMap: 49.8% of cell lines).

This gene encodes a class 1 aminoacyl-tRNA synthetase, mitochondrial leucyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid.

Source: NCBI Gene 23395 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Perrault syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 622 total — 27 pathogenic, 28 likely-pathogenic
• Phenotypes (HPO): 50
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 49.8% of screened cell lines
• MANE Select transcript: NM_015340

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17095
Approved symbol	LARS2
Name	leucyl-tRNA synthetase 2, mitochondrial
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0028, LEURS, MGC26121, mtLeuRS
Ensembl gene	ENSG00000011376
Ensembl biotype	protein_coding
OMIM	604544
Entrez	23395

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 24 protein_coding, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000265537, ENST00000414984, ENST00000430399, ENST00000431023, ENST00000467936, ENST00000474585, ENST00000485461, ENST00000642274, ENST00000645846, ENST00000650792, ENST00000651549, ENST00000652135, ENST00000872206, ENST00000872207, ENST00000872208, ENST00000872209, ENST00000872210, ENST00000872211, ENST00000872212, ENST00000935377, ENST00000935378, ENST00000935379, ENST00000935380, ENST00000935381, ENST00000935382, ENST00000935383, ENST00000935384, ENST00000953711, ENST00000953712, ENST00000953713, ENST00000953714

RefSeq mRNA: 2 — MANE Select: NM_015340 NM_001368263, NM_015340

CCDS: CCDS2728

Canonical transcript exons

ENST00000645846 — 22 exons

Exon	Start	End
ENSE00000967090	45400245	45400373
ENSE00000967091	45417482	45417573
ENSE00001054362	45419669	45419729
ENSE00001078549	45488697	45488812
ENSE00001078555	45446891	45446980
ENSE00001078559	45485692	45485796
ENSE00001078560	45496275	45496373
ENSE00001078563	45500442	45500579
ENSE00001078564	45476468	45476627
ENSE00001078565	45458743	45458886
ENSE00001078566	45474243	45474350
ENSE00001078567	45491517	45491800
ENSE00001346834	45391583	45391648
ENSE00003473281	45523997	45524108
ENSE00003545602	45541829	45541956
ENSE00003591000	45516094	45516276
ENSE00003632619	45520219	45520296
ENSE00003676723	45517903	45518072
ENSE00003682455	45513135	45513235
ENSE00003823831	45388576	45388680
ENSE00003824608	45394433	45394687
ENSE00003841750	45547351	45549407

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 87.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.2920 / max 136.6362, expressed in 1808 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36375	14.5455	1807
36376	0.7465	441

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	87.17	gold quality
oocyte	CL:0000023	87.00	gold quality
adrenal tissue	UBERON:0018303	86.94	gold quality
secondary oocyte	CL:0000655	86.10	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.09	gold quality
mucosa of transverse colon	UBERON:0004991	83.75	gold quality
nephron tubule	UBERON:0001231	83.30	gold quality
caudate nucleus	UBERON:0001873	83.11	gold quality
pigmented layer of retina	UBERON:0001782	83.00	gold quality
prefrontal cortex	UBERON:0000451	82.84	gold quality
ganglionic eminence	UBERON:0004023	82.74	gold quality
nucleus accumbens	UBERON:0001882	82.73	gold quality
rectum	UBERON:0001052	82.65	gold quality
metanephros	UBERON:0000081	82.54	gold quality
renal glomerulus	UBERON:0000074	82.47	gold quality
substantia nigra pars reticulata	UBERON:0001966	82.29	gold quality
islet of Langerhans	UBERON:0000006	82.16	gold quality
colonic mucosa	UBERON:0000317	82.11	gold quality
right adrenal gland	UBERON:0001233	82.04	gold quality
cingulate cortex	UBERON:0003027	82.02	gold quality
putamen	UBERON:0001874	81.98	gold quality
anterior cingulate cortex	UBERON:0009835	81.90	gold quality
right adrenal gland cortex	UBERON:0035827	81.90	gold quality
right frontal lobe	UBERON:0002810	81.88	gold quality
heart left ventricle	UBERON:0002084	81.85	gold quality
endothelial cell	CL:0000115	81.78	gold quality
cardiac ventricle	UBERON:0002082	81.68	gold quality
parotid gland	UBERON:0001831	81.59	gold quality
primary visual cortex	UBERON:0002436	81.54	gold quality
mucosa of sigmoid colon	UBERON:0004993	81.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	6.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4

miRNA regulators (miRDB)

51 targeting LARS2, 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-4283	100.00	66.42	2097
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-5693	99.24	66.67	1106
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-4999-3P	99.11	65.55	424
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-4326	98.97	67.63	962
HSA-MIR-9986	98.91	69.28	1024
HSA-MIR-487A-5P	98.85	69.37	993
HSA-MIR-487B-5P	98.85	69.48	987
HSA-MIR-4763-5P	98.75	63.89	854

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 49.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 22)

• Upregulation of LARS2 is a hallmark of 324A>G mutation. The accumulation of 3243A>G mutation in the brain may have a pathophysiologic role in bipolar disorder and schizophrenia. (PMID:15737668)
• In this study, we provide evidence that the LARS2 gene may represent a novel type 2 diabetes susceptibility gene. (PMID:15919814)
• There was investigated whether overexpression of human mitochondrial LeuRS suppressed translation and respiratory chain defects associated with the pathogenic A3243G mutation in human cells. (PMID:18796578)
• data indicate that inactivation of LARS2 by both genetic and epigenetic mechanisms may be a common and important event in the carcinogenesis of nasopharyngeal carcinoma (PMID:19129950)
• No evidence to support previous data indicating a role in type 2 diabetes susceptibility in humans with LARS2 single nucleotide polymorphisms (PMID:19847392)
• The alteration of aminoacylation tRNA(Leu(UUR)) caused by the A3243G mutation led to mitochondrial translational defects and thereby reduced the aminoacylated efficiencies of tRNA(Leu(UUR)) as well as tRNA(Ala) and tRNA(Met). (PMID:20194621)
• Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. (PMID:23541342)
• Leucyl tRNA synthetase is able to partially rescue defects caused by mutations in non-cognate itochondrial-tRNAs. (PMID:24413189)
• analysis of the CP1 domain in human mitochondrial leucyl-tRNA synthetase (PMID:26272616)
• This represents the first independent replication of the involvement of LARS2 mutations in Perrault syndrome, contributing valuable information for the further understanding of this disease (PMID:26657938)
• ere we present eight families affected by Perrault syndrome. In five families we identified novel or previously reported variants in HSD17B4, LARS2, CLPP and C10orf2 (PMID:26970254)
• IARS2 knockdown inhibits proliferation, suppresses colony formation, and causes cell cycle arrest in AGS cells. (PMID:29071539)
• We concluded that Perrault syndrome patients with LARS2 mutations are at risk for neurologic problems, despite previous notions otherwise. (PMID:29205794)
• We report novel associations between methylation at MSI2 and LARS2 and obesity-related traits. These results provide further insight into mechanisms underlying obesity-related traits, which can enable identification of new biomarkers in obesity-related chronic diseases. (PMID:29762635)
• This study adds LARS2 and KARS pathogenic variants as gene defects that may underlie deafness, ovarian failure, and leukodystrophy with mitochondrial signature. (PMID:30737337)
• The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy. (PMID:32442335)
• LARS2 Regulates Apoptosis via ROS-Mediated Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Ovarian Granulosa Cells. (PMID:35585880)
• Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion. (PMID:35659337)
• Neonatal lactic acidosis explained by LARS2 defect. (PMID:35750896)
• Lin28a induced mitochondrial dysfunction in human granulosa cells via suppressing LARS2 expression. (PMID:36436798)
• [Analysis of perrault syndrome caused by pathogenic variants in LARS2 and HARS2 genes]. (PMID:38186093)
• Exome sequencing reveals pathogenic mutations in the LARS2 and HSD17B4 genes associated with Perrault syndrome and D-bifunctional protein deficiency in Moroccan families. (PMID:39052101)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lars2	ENSDARG00000075337
mus_musculus	Lars2	ENSMUSG00000035202
rattus_norvegicus	Lars2	ENSRNOG00000004760
drosophila_melanogaster	LeuRS-m	FBGN0027085
caenorhabditis_elegans	lars-2	WBGENE00003074

Paralogs (7): IARS2 (ENSG00000067704), LARS1 (ENSG00000133706), VARS2 (ENSG00000137411), MARS1 (ENSG00000166986), IARS1 (ENSG00000196305), VARS1 (ENSG00000204394), MARS2 (ENSG00000247626)

Protein

Protein identifiers

Leucine–tRNA ligase, mitochondrial — Q15031 (reviewed: Q15031)

Alternative names: Leucyl-tRNA synthetase

All UniProt accessions (7): Q15031, A0A2R8Y581, A0A494C1E0, A0A494C1K2, A0A499FJL2, C9JYR8, E9PHM2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the attachment of leucine to its cognate tRNA.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Ubiquitously expressed, but highest expression in tissues with high metabolic rates, such as skeletal muscle, heart, and kidney.

Disease relevance. Perrault syndrome 4 (PRLTS4) [MIM:615300] An autosomal recessive, sex-influenced disorder characterized by sensorineural deafness in both males and females, and ovarian dysgenesis in females. Affected females have primary amenorrhea, streak gonads, and infertility, whereas affected males show normal pubertal development and are fertile. The disease is caused by variants affecting the gene represented in this entry. Hydrops, lactic acidosis, and sideroblastic anemia (HLASA) [MIM:617021] A lethal, multisystem metabolic disorder characterized by severe lactic acidosis, hydrops, and sideroblastic anemia. Additional features include impaired cardiac function, disordered coagulation, pulmonary hypertension, and progressive renal disease. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (2): NP_001355192, NP_056155* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001412	aa-tRNA-synth_I_CS	Conserved_site
IPR002300	aa-tRNA-synth_Ia	Domain
IPR002302	Leu-tRNA-ligase	Family
IPR009008	Val/Leu/Ile-tRNA-synth_edit	Homologous_superfamily
IPR009080	tRNAsynth_Ia_anticodon-bd	Homologous_superfamily
IPR013155	M/V/L/I-tRNA-synth_anticd-bd	Domain
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR025709	Leu_tRNA-synth_edit	Domain

Pfam: PF00133, PF08264, PF13603

Enzyme classification (BRENDA):

• EC 6.1.1.4 — leucine-tRNA ligase (BRENDA: 40 organisms, 173 substrates, 199 inhibitors, 375 Km, 348 kcat entries)

Substrate kinetics (BRENDA)

40 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-LEUCINE	0.0011–0.9	91
TRNALEU	0.0001–0.0273	81
ATP	0.08–5.8	68
TRNAGAGLEU	0.0001–0.0058	21
TRNALEU(UAA)	0.0013–0.0044	10
L-ISOLEUCINE	0.25–14	8
TRNALEUCUN	0.0002–0.025	7
TRNALEUUUR	—	7
TRNAUAALEU	0.0015–0.0025	6
L-LEU	0.008–0.05	5
ILE-TRNALEU	0.002–0.0025	4
L-ISOLEUCYL-TRNALEU	0.0092–0.0173	4
L-METHIONINE	0.983–7.5	3
TRNALEU FROM AQUIFEX AEOLICUS	0.0003–0.0014	3
TRNALEU FROM ESCHERICHIA COLI	0.0008–0.0015	3

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Leu) + L-leucine + ATP = L-leucyl-tRNA(Leu) + AMP + diphosphate (RHEA:11688)

UniProt features (13 total): sequence variant 5, modified residue 3, short sequence motif 2, transit peptide 1, chain 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15031-F1	90.57	0.79

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 (1): 642

Post-translational modifications (3): 68, 236, 711

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-379726	Mitochondrial tRNA aminoacylation
R-HSA-379724	tRNA Aminoacylation
R-HSA-392499	Metabolism of proteins
R-HSA-72766	Translation

MSigDB gene sets: 244 (showing top): ELVIDGE_HYPOXIA_DN, GOBP_AMINO_ACID_ACTIVATION, GOBP_TRNA_METABOLIC_PROCESS, GOBP_MITOCHONDRIAL_TRANSLATION, AAAYRNCTG_UNKNOWN, GOBP_TRANSLATION, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, GARY_CD5_TARGETS_DN, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, TIEN_INTESTINE_PROBIOTICS_24HR_UP, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, GOBP_REGULATION_OF_TRANSLATIONAL_FIDELITY, REACTOME_MITOCHONDRIAL_TRNA_AMINOACYLATION, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN

GO Biological Process (5): tRNA aminoacylation for protein translation (GO:0006418), leucyl-tRNA aminoacylation (GO:0006429), mitochondrial translation (GO:0032543), translation (GO:0006412), aminoacyl-tRNA metabolism involved in translational fidelity (GO:0106074)

GO Molecular Function (6): aminoacyl-tRNA deacylase activity (GO:0002161), leucine-tRNA ligase activity (GO:0004823), ATP binding (GO:0005524), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), ligase activity (GO:0016874)

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

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
tRNA Aminoacylation	1
Translation	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translation	2
mitochondrion	2
catalytic activity, acting on a tRNA	2
tRNA aminoacylation	1
tRNA aminoacylation for protein translation	1
mitochondrial gene expression	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 metabolic process	1
regulation of translational fidelity	1
carboxylic ester hydrolase activity	1
aminoacyl-tRNA metabolism involved in translational fidelity	1
deacylase activity	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ligase activity, forming carbon-oxygen bonds	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3114 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LARS2	KARS1	Q15046	995
LARS2	MARS1	P56192	988
LARS2	MARS2	Q96GW9	988
LARS2	RARS2	Q5T160	987
LARS2	QARS1	P47897	986
LARS2	IARS1	P41252	980
LARS2	TARS2	Q9BW92	979
LARS2	RARS1	P54136	978
LARS2	TARS3	A2RTX5	978
LARS2	TARS1	P26639	977
LARS2	EPRS1	P07814	973
LARS2	IARS2	Q9NSE4	965
LARS2	PARS2	Q7L3T8	963
LARS2	RRAGD	Q9NQL2	921
LARS2	LIMD1	Q9UGP4	907

IntAct

108 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
BCKDHB	DBT	psi-mi:“MI:0914”(association)	0.530
ACAA2	LARS2	psi-mi:“MI:0914”(association)	0.530
SUCLG1	LARS2	psi-mi:“MI:0914”(association)	0.530
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
ISLR	BCKDK	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
HKDC1	LARS2	psi-mi:“MI:0915”(physical association)	0.400
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
TGOLN2	DENND11	psi-mi:“MI:0914”(association)	0.350
DUSP22	POTEF	psi-mi:“MI:0914”(association)	0.350
BSG	METTL15	psi-mi:“MI:0914”(association)	0.350
GLMP	RTL8C	psi-mi:“MI:0914”(association)	0.350
YBEY	NUDT19	psi-mi:“MI:0914”(association)	0.350
ACSM5	NUDT19	psi-mi:“MI:0914”(association)	0.350
NIT1	NUDT19	psi-mi:“MI:0914”(association)	0.350
ATP5F1D		psi-mi:“MI:0914”(association)	0.350
MRPL21		psi-mi:“MI:0914”(association)	0.350
NDUFS7		psi-mi:“MI:0914”(association)	0.350
LIG3	NDUFS6	psi-mi:“MI:0914”(association)	0.350
SDHB	CLPX	psi-mi:“MI:0914”(association)	0.350

BioGRID (184): LARS2 (Affinity Capture-MS), LARS2 (Affinity Capture-MS), LARS2 (Affinity Capture-MS), LARS2 (Affinity Capture-MS), LARS2 (Reconstituted Complex), LARS2 (Affinity Capture-MS), LARS2 (Affinity Capture-MS), LARS2 (Affinity Capture-MS), LARS2 (Affinity Capture-MS), LARS2 (Affinity Capture-MS), LARS2 (Affinity Capture-MS), LARS2 (Affinity Capture-MS), LARS2 (Affinity Capture-MS), LARS2 (Affinity Capture-MS), LARS2 (Affinity Capture-MS)

ESM2 similar proteins: A0JN80, A2RV18, A8MPP1, B5DG51, D3ZG52, D3ZVK1, E9PY46, G3GTP0, I0IUP3, O00329, O35904, P33611, P37202, P48736, P49717, Q0P4R5, Q0V9Q6, Q13057, Q15031, Q17632, Q503I8, Q5F310, Q5R5N8, Q5RDP4, Q5U2P0, Q5U2Z5, Q68FL6, Q6AXC6, Q6GL41, Q6GN11, Q7ZYP6, Q803A6, Q8BGV0, Q8BTF7, Q8C0S1, Q8HY87, Q8MIR4, Q8QHA5, Q8TF46, Q8VDC0

Diamond homologs: A1WYZ7, A2BR45, A2BWL7, A2C242, A2C9U0, A3DEU0, A3PCW8, A4VQZ0, A4XKG9, A4XYW8, A5D416, A5GL71, A5GT82, A5IKQ3, A5VA89, A5W9H9, A6TQK3, A6V0C2, A8F1J5, A8G4T7, A9BAE4, B0C1R1, B0KJW8, B0TBJ3, B1I5R7, B1J150, B1WSK6, B1XP90, B2A6C2, B2J7T9, B7JYA9, B7KCI7, B7V9C9, B8CXR8, B8F9F0, B8FUR3, B8GV13, B8HM05, C0QI75, C0QWR3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ATF4	“up-regulates quantity by expression”	LARS2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 131 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
Complex I biogenesis	6	10.1×	1e-03
Mitochondrial ribosome-associated quality control	8	10.0×	4e-04
Mitochondrial translation	6	8.4×	3e-03
Mitochondrial protein degradation	7	8.2×	1e-03
Respiratory electron transport	8	7.8×	1e-03
Mitochondrial translation initiation	6	7.8×	3e-03
Mitochondrial translation elongation	6	7.8×	3e-03
Aerobic respiration and respiratory electron transport	8	7.2×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial large ribosomal subunit assembly	6	48.8×	1e-06
aerobic respiration	8	16.2×	8e-06
proton motive force-driven mitochondrial ATP synthesis	7	15.1×	7e-05
mitochondrial electron transport, NADH to ubiquinone	5	14.7×	3e-03
mitochondrial translation	9	12.8×	8e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	28
Uncertain significance	212
Likely benign	235
Benign	56

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1185630	NM_015340.4(LARS2):c.1783del (p.Ala595fs)	Pathogenic
1185680	NM_015340.4(LARS2):c.41_42del (p.Leu14fs)	Pathogenic
1342701	NM_015340.4(LARS2):c.1670A>G (p.Tyr557Cys)	Pathogenic
1354734	NM_015340.4(LARS2):c.1540_1541del (p.Lys514fs)	Pathogenic
1407413	NM_015340.4(LARS2):c.186G>A (p.Trp62Ter)	Pathogenic
1928053	NM_015340.4(LARS2):c.2080C>T (p.Arg694Ter)	Pathogenic
1963958	NM_015340.4(LARS2):c.1287del (p.Ala430fs)	Pathogenic
1970089	NM_015340.4(LARS2):c.478C>T (p.Gln160Ter)	Pathogenic
2033454	NM_015340.4(LARS2):c.146_147del (p.Lys49fs)	Pathogenic
203991	NM_015340.4(LARS2):c.1912G>A (p.Glu638Lys)	Pathogenic
2125483	NM_015340.4(LARS2):c.276T>A (p.Tyr92Ter)	Pathogenic
245613	NM_015340.4(LARS2):c.1289C>T (p.Ala430Val)	Pathogenic
2706891	NM_015340.4(LARS2):c.115del (p.Ser39fs)	Pathogenic
2750538	NM_015340.4(LARS2):c.1653G>A (p.Trp551Ter)	Pathogenic
2859536	NM_015340.4(LARS2):c.1181dup (p.Tyr394Ter)	Pathogenic
2859976	NM_015340.4(LARS2):c.380del (p.Gly127fs)	Pathogenic
3247014	NC_000003.11:g.(?45537747)(45537885_?)del	Pathogenic
3601183	NM_015340.4(LARS2):c.1239+1G>A	Pathogenic
3601186	NM_015340.4(LARS2):c.1498G>T (p.Glu500Ter)	Pathogenic
3601187	NM_015340.4(LARS2):c.1623-1G>T	Pathogenic
3601188	NM_015340.4(LARS2):c.2218del (p.Thr740fs)	Pathogenic
3601190	NM_015340.4(LARS2):c.2585_2589dup (p.Asp864fs)	Pathogenic
3690461	NM_015340.4(LARS2):c.1391_1392delinsAA (p.Cys464Ter)	Pathogenic
3695712	NM_015340.4(LARS2):c.2073del (p.Trp691fs)	Pathogenic
431125	NM_015340.4(LARS2):c.371A>T (p.Asn124Ile)	Pathogenic
4729984	NM_015340.4(LARS2):c.1778_1784del (p.Leu593fs)	Pathogenic
55873	NM_015340.4(LARS2):c.1077del (p.Ile360fs)	Pathogenic
1252055	NM_015340.4(LARS2):c.2134C>T (p.Pro712Ser)	Likely pathogenic
1358997	NM_015340.4(LARS2):c.1524-1G>T	Likely pathogenic
1708965	NM_015340.4(LARS2):c.2072G>A (p.Trp691Ter)	Likely pathogenic

SpliceAI

4423 predictions. Top by Δscore:

Variant	Effect	Δscore
3:45394431:AG:A	acceptor_gain	1.0000
3:45394432:GG:G	acceptor_gain	1.0000
3:45394685:GAT:G	donor_gain	1.0000
3:45400243:A:AG	acceptor_gain	1.0000
3:45400244:G:GG	acceptor_gain	1.0000
3:45400244:GAA:G	acceptor_gain	1.0000
3:45400292:T:TA	acceptor_gain	1.0000
3:45400372:AG:A	donor_loss	1.0000
3:45400373:GGTAA:G	donor_loss	1.0000
3:45400374:G:A	donor_loss	1.0000
3:45400375:T:A	donor_loss	1.0000
3:45417472:T:TA	acceptor_gain	1.0000
3:45417473:G:A	acceptor_gain	1.0000
3:45417476:TCCTA:T	acceptor_loss	1.0000
3:45417477:CCTA:C	acceptor_loss	1.0000
3:45417478:CTAG:C	acceptor_loss	1.0000
3:45417479:TA:T	acceptor_loss	1.0000
3:45417480:A:AT	acceptor_loss	1.0000
3:45417569:CAAAG:C	donor_gain	1.0000
3:45417570:AAAGG:A	donor_loss	1.0000
3:45417571:AAG:A	donor_gain	1.0000
3:45417571:AAGGT:A	donor_loss	1.0000
3:45417572:AG:A	donor_gain	1.0000
3:45417572:AGG:A	donor_loss	1.0000
3:45417573:GG:G	donor_gain	1.0000
3:45417573:GGTA:G	donor_loss	1.0000
3:45417574:G:GG	donor_gain	1.0000
3:45417574:GTA:G	donor_loss	1.0000
3:45467250:G:GT	donor_gain	1.0000
3:45476594:G:GT	donor_gain	1.0000

AlphaMissense

5932 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:45496333:T:A	W528R	0.998
3:45496333:T:C	W528R	0.998
3:45417500:T:A	W128R	0.997
3:45417500:T:C	W128R	0.997
3:45496318:T:C	F523L	0.997
3:45496320:T:A	F523L	0.997
3:45496320:T:G	F523L	0.997
3:45500518:C:G	H567D	0.997
3:45400332:A:C	S108R	0.996
3:45400334:C:A	S108R	0.996
3:45400334:C:G	S108R	0.996
3:45500519:A:G	H567R	0.996
3:45541897:T:A	W825R	0.996
3:45541897:T:C	W825R	0.996
3:45491616:T:A	W447R	0.995
3:45491616:T:C	W447R	0.995
3:45458857:T:A	W241R	0.994
3:45458857:T:C	W241R	0.994
3:45474276:T:A	W262R	0.994
3:45474276:T:C	W262R	0.994
3:45500508:T:A	H563Q	0.994
3:45500508:T:G	H563Q	0.994
3:45500510:C:A	A564D	0.994
3:45500520:C:A	H567Q	0.994
3:45500520:C:G	H567Q	0.994
3:45517929:T:A	W691R	0.994
3:45517929:T:C	W691R	0.994
3:45496327:T:C	S526P	0.993
3:45516220:G:C	R663P	0.993
3:45400318:G:C	R103P	0.992

dbSNP variants (sampled 300 via entrez): RS1000002668 (3:45526459 G>A), RS1000037519 (3:45548459 C>T), RS1000098971 (3:45424165 T>C,G), RS1000110803 (3:45411756 T>G), RS1000111075 (3:45413884 G>T), RS1000111949 (3:45472563 A>G), RS1000121709 (3:45472927 A>G), RS1000143166 (3:45520136 T>C), RS1000170747 (3:45404215 G>A,T), RS1000187804 (3:45510013 C>T), RS1000188034 (3:45466431 T>A), RS1000192222 (3:45451492 T>C), RS1000214537 (3:45487464 C>G), RS1000229886 (3:45545240 A>T), RS1000247048 (3:45487311 A>G)

Disease associations

OMIM: gene MIM:604544 | disease phenotypes: MIM:617021, MIM:615300, MIM:233400

GenCC curated gene-disease

Disease	Classification	Inheritance
hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome	Strong	Autosomal recessive
Perrault syndrome 4	Strong	Autosomal recessive
Perrault syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Perrault syndrome	Definitive	AR

Mondo (6): hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome (MONDO:0014869), Perrault syndrome 4 (MONDO:0014126), Perrault syndrome (MONDO:0017312), inborn mitochondrial myopathy (MONDO:0009637), nonsyndromic genetic hearing loss (MONDO:0019497), primary ovarian failure (MONDO:0005387)

Orphanet (6): Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome (Orphanet:528091), Perrault syndrome (Orphanet:2855), Mitochondrial myopathy (Orphanet:206966), Rare genetic deafness (Orphanet:96210), Rare non-syndromic genetic deafness (Orphanet:87884), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000013	Hypoplasia of the uterus
HP:0000175	Cleft palate
HP:0000408	Progressive sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000786	Primary amenorrhea
HP:0000790	Hematuria
HP:0000813	Bicornuate uterus
HP:0000822	Hypertension
HP:0000837	Increased circulating gonadotropin level
HP:0000869	Secondary amenorrhea
HP:0000876	Oligomenorrhea
HP:0000939	Osteoporosis
HP:0001250	Seizure
HP:0001270	Motor delay
HP:0001410	Decreased liver function
HP:0001511	Intrauterine growth retardation
HP:0001513	Obesity
HP:0001518	Small for gestational age
HP:0001519	Disproportionate tall stature
HP:0001541	Ascites
HP:0001562	Oligohydramnios
HP:0001629	Ventricular septal defect
HP:0001643	Patent ductus arteriosus
HP:0001790	Nonimmune hydrops fetalis
HP:0001873	Thrombocytopenia
HP:0001903	Anemia
HP:0001924	Sideroblastic anemia
HP:0001942	Metabolic acidosis
HP:0001978	Extramedullary hematopoiesis

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002481_7	Acne (severe)	3.000000e-06
GCST002740_80	Inflammatory skin disease	5.000000e-07
GCST008758_60	Pre-treatment viral load in HIV-1 infection	4.000000e-16
GCST010698_35	Subcortical volume (min-P)	2.000000e-35
GCST010699_82	Brain morphology (min-P)	3.000000e-15
GCST010701_19	Cortical surface area (MOSTest)	5.000000e-08
GCST010702_119	Subcortical volume (MOSTest)	2.000000e-09
GCST010703_230	Brain morphology (MOSTest)	1.000000e-12
GCST010988_139	Adult body size	4.000000e-09
GCST012251_14	Macular telangiectasia type 2	1.000000e-09
GCST012252_5	Macular telangiectasia type 2	6.000000e-10
GCST90013658_3	Myeloperoxidase-DNA complexes	1.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0010125	viral load
EFO:0004346	neuroimaging measurement
EFO:1002009	macular telangiectasia type 2
EFO:0011039	myeloperoxidase (MPO)-DNA complex measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D017240	Mitochondrial Myopathies	C05.651.460; C10.668.491.500; C18.452.660.560
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105806 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases reaction, decreases expression, increases expression, affects binding	3
Acetaminophen	affects cotreatment, decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	2
Cyclosporine	decreases expression	2
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	increases expression	1
aflatoxin B2	decreases methylation	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	increases methylation	1
NSC 689534	decreases expression, affects binding	1
Atrazine	decreases expression	1
Cadmium	increases abundance, increases expression	1
Copper	affects binding, decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1
Tunicamycin	decreases expression	1
Urethane	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases abundance, increases expression	1
Thapsigargin	decreases expression	1
Copper Sulfate	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4020315	ADMET	Inhibition of human N-terminal 6His-tagged mitochondrial LeuRS expressed in Escherichia coli BL21(DE3) assessed as L-[14C]leucine incorporation in to Escherichia coli tRNA after 20 mins by liquid scintillation counting analysis	Discovery of a Potent and Specific M. tuberculosis Leucyl-tRNA Synthetase Inhibitor: (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol (GSK656). — J Med Chem

Clinical trials (associated diseases)

116 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
NCT03323749	PHASE3	TERMINATED	A Trial to Evaluate Safety and Efficacy of Elamipretide Primary Mitochondrial Myopathy Followed by Open-Label Extension
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00457314	PHASE2	UNKNOWN	The Effects of Exercise Versus Inactivity on People With Mitochondrial Muscle Disease
NCT02255422	PHASE2	COMPLETED	RTA 408 Capsules in Patients With Mitochondrial Myopathy - MOTOR
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04535609	PHASE2	COMPLETED	An Efficacy and Safety Study of 24 Week Treatment With Mavodelpar (REN001) in Primary Mitochondrial Myopathy Patients
NCT04641962	PHASE2	TERMINATED	A Study to Evaluate ASP0367 in Participants With Primary Mitochondrial Myopathy
NCT05590468	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate Vitamin B3 Derivative to Treat Mitochondrial Myopathy
NCT05962333	PHASE2	UNKNOWN	Effect and Safety MABs Administration m.3243A>G Mutation Carriers
NCT06754098	PHASE2	RECRUITING	Doxecitin and Doxribthymine in Adult Subjects With Thymidine Kinase 2 (TK2) Deficiency
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
NCT03862846	PHASE1	TERMINATED	A Study of the Safety of REN001 in Patients With Primary Mitochondrial Myopathy
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
NCT05063721	PHASE1	COMPLETED	MABs Therapy m.3243A>G Mutation Carriers
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
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
NCT05267574	PHASE2/PHASE3	TERMINATED	An Open Label, Long Term Safety Study of REN001 in Primary Mitochondrial Myopathy Patients (Stride Ahead)
NCT02367014	PHASE1/PHASE2	COMPLETED	Safety, Tolerability, and Efficacy of MTP-131 for the Treatment of Mitochondrial Myopathy
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT00004353	Not specified	COMPLETED	Study of the Metabolism of Pyruvate and Related Problems in Patients With Lactic Acidemia
NCT00004770	Not specified	COMPLETED	Pilot Compassionate Use Study of Thioctic Acid Treatment in Mitochondrial Myopathy