FARS2

Summary

FARS2 (phenylalanyl-tRNA synthetase 2, mitochondrial, HGNC:21062) is a protein-coding gene on chromosome 6p25.1, encoding Phenylalanine–tRNA ligase, mitochondrial (O95363). Is responsible for the charging of tRNA(Phe) with phenylalanine in mitochondrial translation. It is a selective cancer dependency (DepMap: 53.6% of cell lines).

This gene encodes a protein that transfers phenylalanine to its cognate tRNA. This protein localizes to the mitochondrion and plays a role in mitochondrial protein translation. Mutations in this gene can cause combined oxidative phosphorylation deficiency 14 (Alpers encephalopathy). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10667 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 638 total — 50 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 75
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 53.6% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_006567

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21062
Approved symbol	FARS2
Name	phenylalanyl-tRNA synthetase 2, mitochondrial
Location	6p25.1
Locus type	gene with protein product
Status	Approved
Aliases	dJ236A3.1, mtPheRS
Ensembl gene	ENSG00000145982
Ensembl biotype	protein_coding
OMIM	611592
Entrez	10667

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 29 protein_coding, 1 nonsense_mediated_decay

ENST00000274680, ENST00000324331, ENST00000445533, ENST00000602691, ENST00000648580, ENST00000897566, ENST00000897567, ENST00000897568, ENST00000897569, ENST00000897570, ENST00000897571, ENST00000897572, ENST00000897573, ENST00000897574, ENST00000897575, ENST00000897576, ENST00000897577, ENST00000897578, ENST00000897579, ENST00000897580, ENST00000897581, ENST00000897582, ENST00000937582, ENST00000937583, ENST00000937584, ENST00000937585, ENST00000954686, ENST00000954687, ENST00000954688, ENST00000954689

RefSeq mRNA: 11 — MANE Select: NM_006567 NM_001318872, NM_001374875, NM_001374876, NM_001374877, NM_001374878, NM_001374879, NM_001375257, NM_001375258, NM_001375259, NM_001375260, NM_006567

CCDS: CCDS4494

Canonical transcript exons

ENST00000274680 — 7 exons

Exon	Start	End
ENSE00000973358	5404542	5404701
ENSE00000973359	5431041	5431172
ENSE00001125682	5368550	5369182
ENSE00001155746	5613169	5613320
ENSE00001155754	5545180	5545340
ENSE00001345246	5771291	5771583
ENSE00003407836	5261513	5261660

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 90.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.1685 / max 132.9220, expressed in 1778 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65588	10.1894	1772
65587	0.9791	567

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
triceps brachii	UBERON:0001509	90.44	silver quality
endothelial cell	CL:0000115	88.54	gold quality
gluteal muscle	UBERON:0002000	88.14	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.12	gold quality
tongue squamous epithelium	UBERON:0006919	87.39	silver quality
skeletal muscle tissue	UBERON:0001134	86.73	gold quality
deltoid	UBERON:0001476	86.69	gold quality
epithelium of bronchus	UBERON:0002031	86.61	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	86.59	gold quality
nasal cavity epithelium	UBERON:0005384	86.51	gold quality
buccal mucosa cell	CL:0002336	86.50	gold quality
quadriceps femoris	UBERON:0001377	86.50	silver quality
vastus lateralis	UBERON:0001379	86.49	silver quality
choroid plexus epithelium	UBERON:0003911	86.45	gold quality
bronchus	UBERON:0002185	86.44	gold quality
sperm	CL:0000019	86.02	silver quality
cervix squamous epithelium	UBERON:0006922	86.00	gold quality
muscle tissue	UBERON:0002385	85.92	gold quality
adrenal tissue	UBERON:0018303	85.83	gold quality
male germ cell	CL:0000015	85.78	silver quality
heart left ventricle	UBERON:0002084	85.68	gold quality
cardiac ventricle	UBERON:0002082	85.58	gold quality
muscle organ	UBERON:0001630	85.54	gold quality
epithelium of nasopharynx	UBERON:0001951	85.21	gold quality
vena cava	UBERON:0004087	85.20	silver quality
myocardium	UBERON:0002349	85.17	silver quality
calcaneal tendon	UBERON:0003701	85.17	gold quality
muscle of leg	UBERON:0001383	85.13	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	85.11	gold quality
left ventricle myocardium	UBERON:0006566	85.01	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.71

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): QRICH1

miRNA regulators (miRDB)

12 targeting FARS2, 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-6809-3P	99.91	71.45	3814
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-3151-3P	97.80	66.16	479
HSA-MIR-5699-5P	97.36	67.03	1014
HSA-MIR-335-5P	97.10	68.12	1022

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 53.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 18)

• The recombinant human enzyme has been purified to homogeneity and crystallized in complex with phenylalanine and ATP. (PMID:17768348)
• Formation of the PheRS-tRNAPhe complex in human mitochondria must be accompanied by considerable rearrangement of the anticodon binding domain upon tRNA binding. (PMID:18611382)
• Mitochondrial and cytoplasmic phenylalanyl-tRNA synthetases (HsmtPheRS and HsctPheRS, respectively) catalyze direct attachment of m-Tyr to tRNA(Phe). (PMID:19549855)
• these results indicate that conformational flexibility of the two functional modules in mtPheRS is essential for its phenylalanylation activity. (PMID:19737557)
• Two phenylalanyl-tRNA synthetase variants Ser57Cys and Asp280Ser both display wild-type aminoacylation activity and stability with respect to their free energies of unfolding, but are less stable at low hydrogen-ion concentration (pH). (PMID:21601574)
• the three FARS2 mutations directly impair aminoacylation function and stability of mtPheRS, leading to a decrease in overall tRNA charging capacity. (PMID:22833457)
• this study expands the phenotypic spectrum of FARS2 related disease and emphasizes intragenic deletion in the list of causative mutations. (PMID:25851414)
• A newly identified missense mutation in FARS2 causes autosomal-recessive spastic paraplegia. (PMID:26553276)
• in patients with drug-resistant infantile spasm syndrome, associated with focal seizures, mild metabolic changes, and cerebral atrophy with volume loss of white matter on MRI, mutations in FARS2 should be considered. (PMID:27549011)
• Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2 have been described. (PMID:28419689)
• Based on the phenotypic data of previously reported subjects and the two subjects reported here, we conclude that FARS2 deficiency can be associated with two phenotypes: (i) an epileptic phenotype, and (ii) a spastic paraplegia phenotype. (PMID:29126765)
• The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in trans with a missense variant. (PMID:30177229)
• the presence of aggregation-prone insoluble human mitochondrial phenylalanyl-tRNA synthetase (HsmitPheRS) variants could have a detrimental impact on organellar translation, and potentially impact normal mitochondrial function in Alpers encephalopathy (PMID:31241862)
• Breaking a single hydrogen bond in the mitochondrial tRNA(Phe) -PheRS complex leads to phenotypic pleiotropy of human disease. (PMID:32115907)
• Novel FARS2 variants in patients with early onset encephalopathy with or without epilepsy associated with long survival. (PMID:33168986)
• Phenotypic diversity of brain MRI patterns in mitochondrial aminoacyl-tRNA synthetase mutations. (PMID:33972171)
• Two Chinese siblings of combined oxidative phosphorylation deficiency 14 caused by compound heterozygous variants in FARS2. (PMID:36155627)
• FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System. (PMID:38362779)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fars2	ENSDARG00000091247
mus_musculus	Fars2	ENSMUSG00000021420
rattus_norvegicus	Fars2	ENSRNOG00000016135
drosophila_melanogaster	PheRS-m	FBGN0275436
caenorhabditis_elegans		WBGENE00013361

Paralogs (2): FARSA (ENSG00000179115), FDXACB1 (ENSG00000255561)

Protein

Protein identifiers

Phenylalanine–tRNA ligase, mitochondrial — O95363 (reviewed: O95363)

Alternative names: Phenylalanyl-tRNA synthetase

All UniProt accessions (4): A0A3B3ITR6, O95363, Q5JRF7, R4GMX6

UniProt curated annotations — full annotation on UniProt →

Function. Is responsible for the charging of tRNA(Phe) with phenylalanine in mitochondrial translation. To a lesser extent, also catalyzes direct attachment of m-Tyr (an oxidized version of Phe) to tRNA(Phe), thereby opening the way for delivery of the misacylated tRNA to the ribosome and incorporation of ROS-damaged amino acid into proteins.

Subunit / interactions. Monomer.

Subcellular location. Mitochondrion matrix. Mitochondrion.

Disease relevance. Combined oxidative phosphorylation deficiency 14 (COXPD14) [MIM:614946] A severe multisystemic autosomal recessive disorder characterized by neonatal onset of global developmental delay, refractory seizures, and lactic acidosis. Biochemical studies show deficiencies of multiple mitochondrial respiratory enzymes. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 77, autosomal recessive (SPG77) [MIM:617046] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (11): NP_001305801, NP_001361804, NP_001361805, NP_001361806, NP_001361807, NP_001361808, NP_001362186, NP_001362187, NP_001362188, NP_001362189, NP_006558* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002319	Phenylalanyl-tRNA_Synthase	Domain
IPR004530	Phe-tRNA-synth_IIc_mito	Family
IPR005121	Fdx_antiC-bd	Domain
IPR006195	aa-tRNA-synth_II	Domain
IPR036690	Fdx_antiC-bd_sf	Homologous_superfamily
IPR045864	aa-tRNA-synth_II/BPL/LPL	Homologous_superfamily

Pfam: PF01409, PF03147

Enzyme classification (BRENDA):

• EC 6.1.1.20 — phenylalanine-tRNA ligase (BRENDA: 45 organisms, 151 substrates, 239 inhibitors, 149 Km, 73 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
L-PHENYLALANINE	0.0003–11	28
TRNAPHE	0.0001–0.018	27
ATP	0.0058–2.5	26
PHE	0.0004–0.083	12
L-PHE	0.0018–0.05	11
2-CHLOROADENOSINE 5’-TRIPHOSPHATE	0.05–0.2	8
L-TYROSINE	0.32–3	7
2’-DEOXYADENOSINE 5’-TRIPHOSPHATE	0.085–0.4	4
3,4-DIHYDROXY-L-PHENYLALANINE	0.38–0.65	3
3’-DEOXYADENOSINE 5’-TRIPHOSPHATE	0.82–1	2
DL-M-TYROSINE	0.012–0.13	2
(S-PA)TRNAPHE	0.0002	1
(S-PG)TRNAPHE	0.0002	1
2-DEOXYADENOSINE 5’-TRIPHOSPHATE	1.54	1
2-L-NAPHTHYLALANINE	2	1

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Phe) + L-phenylalanine + ATP = L-phenylalanyl-tRNA(Phe) + AMP + diphosphate + H(+) (RHEA:19413)

UniProt features (61 total): helix 20, strand 19, sequence variant 6, binding site 6, turn 4, sequence conflict 2, transit peptide 1, chain 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
5MGW	X-RAY DIFFRACTION	1.46
8P8X	X-RAY DIFFRACTION	1.46
5MGH	X-RAY DIFFRACTION	1.87
5MGU	X-RAY DIFFRACTION	1.89
5MGV	X-RAY DIFFRACTION	2.05
3CMQ	X-RAY DIFFRACTION	2.2
3TEG	X-RAY DIFFRACTION	2.2
3HFV	X-RAY DIFFRACTION	2.6
3TUP	X-RAY DIFFRACTION	3.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95363-F1	90.17	0.86

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 (6): 157–160; 179; 186–188; 193–195; 287; 312

Post-translational modifications (1): 202

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: 254 (showing top): BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, GOBP_AMINO_ACID_ACTIVATION, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_TRANSLATION, chr6p25, BROWNE_HCMV_INFECTION_14HR_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, AFFAR_YY1_TARGETS_DN, REACTOME_MITOCHONDRIAL_TRNA_AMINOACYLATION, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, ACEVEDO_LIVER_CANCER_UP, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_DN, GOBP_TRNA_PROCESSING

GO Biological Process (5): tRNA aminoacylation for protein translation (GO:0006418), phenylalanyl-tRNA aminoacylation (GO:0006432), tRNA processing (GO:0008033), translation (GO:0006412), tRNA aminoacylation (GO:0043039)

GO Molecular Function (7): tRNA binding (GO:0000049), phenylalanine-tRNA ligase activity (GO:0004826), ATP binding (GO:0005524), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), protein binding (GO:0005515), ligase activity (GO:0016874)

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

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
tRNA metabolic process	2
translation	1
tRNA aminoacylation	1
tRNA aminoacylation for protein translation	1
RNA processing	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
amino acid activation	1
RNA binding	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, acting on a tRNA	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2010 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FARS2	AARS1	P49588	855
FARS2	YARS2	Q9Y2Z4	811
FARS2	EARS2	Q5JPH6	810
FARS2	AARS2	Q5JTZ9	807
FARS2	NARS2	Q96I59	807
FARS2	LARS2	Q15031	798
FARS2	DARS2	Q6PI48	793
FARS2	MARS2	Q96GW9	777
FARS2	PARS2	Q7L3T8	777
FARS2	VARS1	P26640	774
FARS2	TARS2	Q9BW92	774
FARS2	IARS2	Q9NSE4	774
FARS2	RARS2	Q5T160	773
FARS2	YARS1	P54577	772
FARS2	FARSB	Q9NSD9	766

IntAct

327 interactions, top by confidence:

A	B	Type	Score
CALCOCO2	FARS2	psi-mi:“MI:0915”(physical association)	0.780
FARS2	APPL1	psi-mi:“MI:0915”(physical association)	0.780
FARS2	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.780
APPL1	FARS2	psi-mi:“MI:0915”(physical association)	0.780
FARS2	RCBTB2	psi-mi:“MI:0915”(physical association)	0.720
FARS2	KRTAP10-7	psi-mi:“MI:0915”(physical association)	0.720
KRTAP10-9	FARS2	psi-mi:“MI:0915”(physical association)	0.720
KRT40	FARS2	psi-mi:“MI:0915”(physical association)	0.720
MID2	FARS2	psi-mi:“MI:0915”(physical association)	0.720
FARS2	IKZF3	psi-mi:“MI:0915”(physical association)	0.720
RCBTB2	FARS2	psi-mi:“MI:0915”(physical association)	0.720
KRTAP10-7	FARS2	psi-mi:“MI:0915”(physical association)	0.720
FARS2	MID2	psi-mi:“MI:0915”(physical association)	0.720
FARS2	KRTAP10-9	psi-mi:“MI:0915”(physical association)	0.720
FARS2	KRT40	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (169): FARS2 (Two-hybrid), FARS2 (Two-hybrid), FARS2 (Two-hybrid), FARS2 (Two-hybrid), FARS2 (Two-hybrid), FARS2 (Two-hybrid), FARS2 (Two-hybrid), FARS2 (Two-hybrid), FARS2 (Two-hybrid), MID2 (Two-hybrid), IKZF3 (Two-hybrid), APPL1 (Two-hybrid), ADAMTSL4 (Two-hybrid), AGTRAP (Two-hybrid), TRIM54 (Two-hybrid)

ESM2 similar proteins: A2RTX5, A4QP75, A5D7V9, A6QNM8, A6QPU5, D3ZX08, F4IFC5, O04630, O43011, O95363, P07178, P12081, P26639, P34183, P36776, P49590, P70076, Q0V9S0, Q2KI84, Q3KRD0, Q3UQ84, Q3ZBV8, Q4R816, Q59HJ6, Q5M7W7, Q5R4R2, Q5R5E5, Q5XHY5, Q61035, Q66HG3, Q68FW7, Q6AYQ3, Q6E6B4, Q6PI48, Q86AS6, Q8BGQ7, Q8BGV0, Q8BIP0, Q8BLY2, Q8CFI5

Diamond homologs: A0KKP5, A1A1X6, A1JML2, A1S702, A2RN75, A4SMA8, A4TIL5, A4W9M7, A4XKJ8, A5F1W4, A5VKV1, A6TAI3, A6V489, A7FHG5, A7HLU6, A7MNY9, A7NCN7, A8GDQ9, A8GS12, A9KGB7, A9KHY1, A9N8K1, A9R0A4, B0C6I2, B0U0C4, B0U5D9, B0V5Q6, B0VV85, B1JJ21, B2G885, B2I9P4, B2IUA1, B2K664, B2VEL4, B4ETL0, B4RS43, B5FDX4, B5XQD0, B6EN08, B6IZG0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
QRICH1	“up-regulates quantity by expression”	FARS2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 99 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
Keratinization	10	9.3×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	50
Likely pathogenic	26
Uncertain significance	290
Likely benign	178
Benign	47

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070492	NC_000006.11:g.(?5368804)(5369425_?)del	Pathogenic
1076463	NC_000006.11:g.(?5545403)(5545583_?)del	Pathogenic
1076465	NC_000006.11:g.(?5368784)(5545593_?)del	Pathogenic
1351885	NM_006567.5(FARS2):c.999G>A (p.Trp333Ter)	Pathogenic
1375428	NM_006567.5(FARS2):c.425del (p.Asp142fs)	Pathogenic
1450668	NC_000006.11:g.(?5260861)(5369435_?)del	Pathogenic
1450690	NC_000006.11:g.(?5339261)(5404834_?)del	Pathogenic
1452947	NM_006567.5(FARS2):c.694del (p.Thr232fs)	Pathogenic
1455928	NM_006567.5(FARS2):c.877del (p.Gly292_Val293insTer)	Pathogenic
1460186	NC_000006.11:g.(?5431254)(5653711_?)del	Pathogenic
1946683	NM_006567.5(FARS2):c.929G>A (p.Trp310Ter)	Pathogenic
2092976	NM_006567.5(FARS2):c.497dup (p.Leu168fs)	Pathogenic
2134155	NM_006567.5(FARS2):c.1110G>A (p.Trp370Ter)	Pathogenic
2425605	NC_000006.11:g.(?5368804)(5404954_?)del	Pathogenic
2425606	NC_000006.11:g.(?5404755)(5431425_?)del	Pathogenic
2425607	NC_000006.11:g.(?5404755)(5545593_?)del	Pathogenic
2425613	NC_000006.11:g.(?5368804)(5369435_?)del	Pathogenic
2425614	NC_000006.11:g.(?5216831)(5431425_?)del	Pathogenic
2500183	NC_000006.11:g.(?5172693)(5459957_?)del	Pathogenic
253159	NM_006567.5(FARS2):c.424G>T (p.Asp142Tyr)	Pathogenic
2674634	NM_006567.5:c.(?-4)(612+185_613-1)del	Pathogenic
2691634	NC_000006.11:g.(?5261745)(5545574_5613401)del	Pathogenic
2771426	NM_006567.5(FARS2):c.1218-73_1289delinsC	Pathogenic
2861363	NM_006567.5(FARS2):c.11C>G (p.Ser4Ter)	Pathogenic
3246032	NC_000006.11:g.(?5109657)(5771662_?)del	Pathogenic
3246034	NC_000006.12:g.(?5613149)(5613340_?)del	Pathogenic
3246035	NC_000006.11:g.(?5545393)(5613573_?)del	Pathogenic
3621670	NM_006567.5(FARS2):c.63del (p.His22fs)	Pathogenic
3666334	NM_006567.5(FARS2):c.1A>G (p.Met1Val)	Pathogenic
389162	NM_006567.5(FARS2):c.646C>T (p.Gln216Ter)	Pathogenic

SpliceAI

5239 predictions. Top by Δscore:

Variant	Effect	Δscore
6:5368547:CAGA:C	acceptor_loss	1.0000
6:5368548:A:AG	acceptor_gain	1.0000
6:5368548:A:AT	acceptor_loss	1.0000
6:5368549:G:GG	acceptor_gain	1.0000
6:5369179:TGAGG:T	donor_loss	1.0000
6:5369180:GAGGT:G	donor_loss	1.0000
6:5369181:AGGTG:A	donor_loss	1.0000
6:5369182:GGT:G	donor_loss	1.0000
6:5369183:GTGA:G	donor_loss	1.0000
6:5369184:T:A	donor_loss	1.0000
6:5404537:TACA:T	acceptor_loss	1.0000
6:5404539:CAGTT:C	acceptor_loss	1.0000
6:5404540:A:AG	acceptor_gain	1.0000
6:5404540:A:AT	acceptor_loss	1.0000
6:5404541:G:GA	acceptor_gain	1.0000
6:5404541:G:GC	acceptor_loss	1.0000
6:5404541:GT:G	acceptor_gain	1.0000
6:5404541:GTT:G	acceptor_gain	1.0000
6:5404541:GTTA:G	acceptor_gain	1.0000
6:5404541:GTTAT:G	acceptor_gain	1.0000
6:5404698:GATG:G	donor_gain	1.0000
6:5431027:T:TA	acceptor_gain	1.0000
6:5431031:A:AG	acceptor_gain	1.0000
6:5431032:A:G	acceptor_gain	1.0000
6:5545172:A:AG	acceptor_gain	1.0000
6:5545178:A:AG	acceptor_gain	1.0000
6:5545179:G:GG	acceptor_gain	1.0000
6:5545338:CAGG:C	donor_loss	1.0000
6:5545339:AG:A	donor_loss	1.0000
6:5545340:GGT:G	donor_loss	1.0000

AlphaMissense

2992 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:5431076:T:C	F270L	0.996
6:5431078:T:A	F270L	0.996
6:5431078:T:G	F270L	0.996
6:5404657:T:C	L243P	0.995
6:5369106:G:T	R179M	0.994
6:5431055:T:A	W263R	0.994
6:5431055:T:C	W263R	0.994
6:5369028:G:C	R153T	0.993
6:5369029:A:C	R153S	0.993
6:5369029:A:T	R153S	0.993
6:5369102:T:G	Y178D	0.993
6:5771317:G:C	R415P	0.993
6:5368945:C:A	N125K	0.992
6:5368945:C:G	N125K	0.992
6:5368946:T:C	F126L	0.992
6:5368948:T:A	F126L	0.992
6:5368948:T:G	F126L	0.992
6:5369106:G:C	R179T	0.992
6:5431070:T:C	F268L	0.992
6:5431072:C:A	F268L	0.992
6:5431072:C:G	F268L	0.992
6:5545225:A:T	E317V	0.992
6:5545234:C:A	A320D	0.992
6:5545302:T:C	F343L	0.992
6:5545304:C:A	F343L	0.992
6:5545304:C:G	F343L	0.992
6:5771313:T:G	Y414D	0.992
6:5369109:G:C	R180P	0.991
6:5369141:T:C	F191L	0.991
6:5369143:C:A	F191L	0.991

dbSNP variants (sampled 300 via entrez): RS1000011173 (6:5483195 C>T), RS1000037523 (6:5653318 C>A), RS1000064205 (6:5333435 T>G), RS1000069792 (6:5415866 C>T), RS1000077859 (6:5693343 C>A,G), RS1000085162 (6:5540011 A>C,G), RS1000090665 (6:5407403 G>GT), RS1000092624 (6:5368403 C>A), RS1000097681 (6:5376603 T>A,C), RS1000100950 (6:5269842 G>A,T), RS1000102278 (6:5743156 C>A,G,T), RS1000102897 (6:5312808 C>G), RS1000109528 (6:5480134 C>G), RS1000113955 (6:5672575 T>G), RS1000120234 (6:5650102 G>A,C)

Disease associations

OMIM: gene MIM:611592 | disease phenotypes: MIM:614946, MIM:617046, MIM:181500, MIM:256000, MIM:615595, MIM:104200

GenCC curated gene-disease

Disease	Classification	Inheritance
metabolic disease	Definitive	Autosomal recessive
combined oxidative phosphorylation defect type 14	Strong	Autosomal recessive
hereditary spastic paraplegia 77	Strong	Autosomal recessive
mitochondrial oxidative phosphorylation disorder	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
Leigh syndrome	Moderate	AR
mitochondrial disease	Definitive	AR

Mondo (9): combined oxidative phosphorylation defect type 14 (MONDO:0013986), hereditary spastic paraplegia 77 (MONDO:0014882), schizophrenia (MONDO:0005090), Leigh syndrome (MONDO:0009723), combined oxidative phosphorylation deficiency 19 (MONDO:0014269), autosomal dominant Alport syndrome (MONDO:0007086), intellectual disability (MONDO:0001071), mitochondrial oxidative phosphorylation disorder (MONDO:0016387), metabolic disease (MONDO:0005066)

Orphanet (8): Combined oxidative phosphorylation defect type 14 (Orphanet:319519), Autosomal recessive spastic paraplegia type 77 (Orphanet:466722), Leigh syndrome (Orphanet:506), Severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency (Orphanet:397593), Alport syndrome (Orphanet:63), Autosomal dominant Alport syndrome (Orphanet:88918), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000020	Urinary incontinence
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000365	Hearing impairment
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000675	Macrodontia of permanent maxillary central incisor
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001344	Absent speech
HP:0001385	Hip dysplasia
HP:0001510	Growth delay
HP:0001522	Death in infancy
HP:0001873	Thrombocytopenia
HP:0001903	Anemia
HP:0002059	Cerebral atrophy
HP:0002061	Lower limb spasticity
HP:0002067	Bradykinesia
HP:0002068	Neuromuscular dysphagia
HP:0002080	Intention tremor
HP:0002119	Ventriculomegaly

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001957_17	Obesity (early onset extreme)	5.000000e-07
GCST002938_11	Copper levels	9.000000e-07
GCST004032_5	JT interval (sulfonylurea treatment interaction)	4.000000e-07
GCST005577_3	Change in glucose in response to thiazide diuretic treatment in hypertension	2.000000e-07
GCST008163_100	Height	7.000000e-06
GCST009277_8	Subjective response to placebo treatment in childhood asthma (change in cough/wheeze)	8.000000e-06
GCST009391_626	Metabolite levels	4.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007885	JT interval
EFO:0007922	response to sulfonylurea
EFO:0004468	glucose measurement
EFO:0008344	response to placebo
EFO:0010068	respiratory symptom change measurement
EFO:0010502	indoxyl sulfate measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
D008659	Metabolic Diseases	C18.452

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2511 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs17140129	FARS2		0.00	0

ChEMBL bioactivities

9 potent at pChembl≥5 of 13 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.77	IC50	170	nM	CHEMBL281860
6.58	IC50	260	nM	CHEMBL281860
6.33	IC50	470	nM	CHEMBL284654
6.29	IC50	510	nM	CHEMBL284654
5.70	IC50	2000	nM	CHEMBL27258
5.58	IC50	2600	nM	CHEMBL283182
5.51	IC50	3100	nM	CHEMBL283182
5.31	IC50	4900	nM	CHEMBL25737
5.30	IC50	5000	nM	CHEMBL27258

PubChem BioAssay actives

9 with measured affinity, of 35 total; 5 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
(1S,2S,9S,12S,13R,14R)-N-(3,4-dichlorophenyl)-2-hydroxy-11-oxo-14-phenyl-10,15-dioxatetracyclo[7.6.0.01,12.03,8]pentadeca-3,5,7-triene-13-carboxamide	157612: Compound was evaluated for the inhibitory activity against Escherichia coli phenylalanyl-tRNA synthetase	ic50	0.1700	uM
(1S,2R,9S,12S,13R,14R)-N-(3,4-dichlorophenyl)-2-hydroxy-11-oxo-14-phenyl-10,15-dioxatetracyclo[7.6.0.01,12.03,8]pentadeca-3,5,7-triene-13-carboxamide	157612: Compound was evaluated for the inhibitory activity against Escherichia coli phenylalanyl-tRNA synthetase	ic50	0.4700	uM
(1R,3aS,6aR)-5-(3,4-dichlorophenyl)-1-phenylspiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	157612: Compound was evaluated for the inhibitory activity against Escherichia coli phenylalanyl-tRNA synthetase	ic50	2.0000	uM
(1R,9S,12S,13R,14R)-N-(3,4-dichlorophenyl)-2,11-dioxo-14-phenyl-10,15-dioxatetracyclo[7.6.0.01,12.03,8]pentadeca-3,5,7-triene-13-carboxamide	157613: Compound was evaluated for the inhibitory activity against Staphylococcus aureus phenylalanyl-tRNA synthetase	ic50	2.6000	uM
(1S,12R,13S,14R)-N-(3,4-dichlorophenyl)-2-hydroxy-11-oxo-14-phenyl-10,15-dioxatetracyclo[7.6.0.01,12.03,8]pentadeca-3,5,7-triene-13-carboxamide	157612: Compound was evaluated for the inhibitory activity against Escherichia coli phenylalanyl-tRNA synthetase	ic50	4.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	8
Valproic Acid	affects cotreatment, increases expression, decreases methylation	4
Aflatoxin B1	affects expression, affects methylation, decreases expression, increases methylation	4
bisphenol A	affects cotreatment, decreases methylation, decreases expression	2
Acetaminophen	affects cotreatment, decreases expression	2
Cisplatin	affects expression, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
aristolochic acid I	increases expression, decreases expression	1
methyleugenol	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
aflatoxin B2	decreases methylation	1
nickel sulfate	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
teriflunomide	decreases expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
Decitabine	affects expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	decreases expression	1
Benzene	decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Fluorouracil	decreases expression	1
Formaldehyde	decreases expression	1
Lipopolysaccharides	decreases expression, affects cotreatment	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL768844	Binding	Compound was evaluated for the inhibitory activity against Escherichia coli phenylalanyl-tRNA synthetase	A series of heterocyclic inhibitors of phenylalanyl-tRNA synthetases with antibacterial activity. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00192621	PHASE4	COMPLETED	Seronegatives and Metabolic Abnormalities Protocol 2 (SAMA002): Study to Compare the Effect of Kaletra and Combivir® in HIV-Negative Healthy Subjects
NCT01443806	PHASE4	COMPLETED	Characterisation of the Human Carboxylesterase 1 (CES1) Mutations in Thailand
NCT02645279	PHASE4	UNKNOWN	Comparison of Oral 30 % Dextrose and iv Midazolam Sedation During MRI in Neonates
NCT04653779	PHASE4	UNKNOWN	A Clinical Trial to Evaluate the Preference Regarding Convenience of Medication and Efficacy/Safety of SUGAMET®XR Tablet 5/1000mg
NCT05084079	PHASE4	UNKNOWN	Different Initial Insulin Dose Regimens on Time to Achieve Glycemic Targets and Treatment Safety in SIIT
NCT05855577	PHASE4	NOT_YET_RECRUITING	Motor Function Efficacy of Pharmacological Treatments Targeting Energy Metabolism, in Parkinson’s Patients
NCT06003153	PHASE4	RECRUITING	GLUCOSE-MGH: Genetic Links Understood Through Challenge With Oral Semaglutide Exposure at MGH
NCT06009653	PHASE4	WITHDRAWN	Effects of Tirzepatide Plus Intensive Lifestyle Therapy on Body Weight and Metabolic Health in Latinos With Obesity
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients