YARS2

Summary

YARS2 (tyrosyl-tRNA synthetase 2, HGNC:24249) is a protein-coding gene on chromosome 12p11.21, encoding Tyrosine–tRNA ligase, mitochondrial (Q9Y2Z4). Catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr). It is a common-essential gene (DepMap: required in 95.0% of cancer cell lines).

This gene encodes a mitochondrial protein that catalyzes the attachment of tyrosine to tRNA(Tyr). Mutations in this gene are associated with myopathy with lactic acidosis and sideroblastic anemia type 2 (MLASA2).

Source: NCBI Gene 51067 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 366 total — 24 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 46
• Cancer dependency (DepMap): dependent in 95.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_001040436

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24249
Approved symbol	YARS2
Name	tyrosyl-tRNA synthetase 2
Location	12p11.21
Locus type	gene with protein product
Status	Approved
Aliases	FLJ13995, CGI-04, mt-TyrRS
Ensembl gene	ENSG00000139131
Ensembl biotype	protein_coding
OMIM	610957
Entrez	51067

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000324868, ENST00000548490, ENST00000551673, ENST00000874022, ENST00000874023

RefSeq mRNA: 1 — MANE Select: NM_001040436 NM_001040436

CCDS: CCDS31770

Canonical transcript exons

ENST00000324868 — 5 exons

Exon	Start	End
ENSE00000936513	32755096	32755897
ENSE00000936514	32753918	32754085
ENSE00000936515	32750719	32750874
ENSE00001266823	32746544	32747363
ENSE00003479347	32749937	32750107

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 97.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.5083 / max 105.5101, expressed in 1786 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130408	16.6912	1783
130407	0.8170	542

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	97.85	gold quality
secondary oocyte	CL:0000655	96.41	gold quality
endothelial cell	CL:0000115	92.04	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.30	gold quality
mucosa of transverse colon	UBERON:0004991	89.04	gold quality
adrenal tissue	UBERON:0018303	87.30	gold quality
ventricular zone	UBERON:0003053	86.98	gold quality
endometrium	UBERON:0001295	86.29	gold quality
gingival epithelium	UBERON:0001949	86.02	silver quality
cervix squamous epithelium	UBERON:0006922	85.92	silver quality
right adrenal gland cortex	UBERON:0035827	85.52	gold quality
stromal cell of endometrium	CL:0002255	85.40	gold quality
ganglionic eminence	UBERON:0004023	85.26	gold quality
right adrenal gland	UBERON:0001233	85.25	gold quality
cortical plate	UBERON:0005343	84.98	gold quality
granulocyte	CL:0000094	84.82	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.70	gold quality
squamous epithelium	UBERON:0006914	84.44	silver quality
esophagus mucosa	UBERON:0002469	84.27	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.25	gold quality
gastrocnemius	UBERON:0001388	84.12	gold quality
prefrontal cortex	UBERON:0000451	84.00	gold quality
gingiva	UBERON:0001828	84.00	silver quality
minor salivary gland	UBERON:0001830	83.81	gold quality
epithelium of esophagus	UBERON:0001976	83.72	silver quality
saliva-secreting gland	UBERON:0001044	83.69	gold quality
rectum	UBERON:0001052	83.67	gold quality
muscle of leg	UBERON:0001383	83.67	gold quality
esophagus squamous epithelium	UBERON:0006920	83.61	silver quality
oral cavity	UBERON:0000167	83.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.75

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, QRICH1

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 95.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 14)

• The gene for mitochondrial tyrosyl-tRNA synthetase is described and the initial characterization of the enzyme is reported. Genes for the remaining missing synthetases have also been found with the exception of human glutaminyl-tRNA synthetase. (PMID:15779907)
• first example of a TyrRS lacking specificity toward N1-N72 and thus of a TyrRS disobeying the identity rules (PMID:15840810)
• the apparent occurrence of an unusual TG 3’ splice site in intron 5 is discussed (PMID:17672918)
• the structure of a strictly mitochondrial human synthetase, namely tyrosyl-tRNA synthetase (mt-TyrRS), in complex with an adenylate analog at 2.2 A resolution (PMID:17997975)
• The YARS2 mutation reported here is an alternative cause of MLASA. (PMID:20598274)
• The study confirms mutations in YARS2 as a cause of MLASA and shows that, like some of the cytoplasmic ARSs, mitochondrial ARSs occur in high-molecular-weight complexes. (PMID:22504945)
• Data identified novel YARS2 mutations and noted marked phenotypic variability among YARS2 MLASA patients, with phenotypes ranging from mild to lethal, suggesting that the background mtDNA haplotype may be contributing to the phenotypic variability. (PMID:24344687)
• The mutation in YARS2 gene is a nuclear modifier for the phenotypic manifestation of Leber’s hereditary optic neuropathy-associated mitochondrial DNA mutation. (PMID:26647310)
• The p.Leu392Ser variant is likely a newly identified founder YARS2 mutation in mitochondrial myopathy. (PMID:28395030)
• tyrosyl-tRNA synthetase 2 tyrosine (PMID:29976739)
• Data suggest that biallelic tyrosyl-tRNA synthetase 2 (YARS2) variants, including severe loss-of-function alleles should be considered as a cause of isolated congenital sideroblastic anemia, as well as the myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2) syndromic phenotype. (PMID:30026338)
• findings provide molecular-level insights into the pathophysiology of maternally transmitted deafness arising from the synergy between tRNA(Ser(UCN)) and mitochondrial YARS mutations (PMID:31685661)
• Targeting mitochondrial tyrosyl-tRNA synthetase YARS2 suppresses colorectal cancer progression. (PMID:36154909)
• Nuclear modifier YARS2 allele correction restored retinal ganglion cells-specific deficiencies in Leber’s hereditary optic neuropathy. (PMID:36611011)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	yars2	ENSDARG00000077299
mus_musculus	Yars2	ENSMUSG00000022792
rattus_norvegicus	Yars2	ENSRNOG00000025252
drosophila_melanogaster	TyrRS-m	FBGN0035064
caenorhabditis_elegans		WBGENE00006968

Protein

Protein identifiers

Tyrosine–tRNA ligase, mitochondrial — Q9Y2Z4 (reviewed: Q9Y2Z4)

Alternative names: Tyrosyl-tRNA synthetase

All UniProt accessions (2): Q9Y2Z4, H0YHS6

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr).

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion matrix.

Disease relevance. Myopathy with lactic acidosis and sideroblastic anemia 2 (MLASA2) [MIM:613561] A rare oxidative phosphorylation disorder specific to skeletal muscle and bone marrow. Affected individuals manifest sideroblastic anemia, progressive lethargy, muscle weakness, and exercise intolerance associated with persistent lactic acidemia. 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 (1): NP_001035526* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001412	aa-tRNA-synth_I_CS	Conserved_site
IPR002305	aa-tRNA-synth_Ic	Family
IPR002307	Tyr-tRNA-ligase	Family
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR024088	Tyr-tRNA-ligase_bac-type	Family
IPR036986	S4_RNA-bd_sf	Homologous_superfamily

Pfam: PF00579

Enzyme classification (BRENDA):

• EC 6.1.1.1 — tyrosine-tRNA ligase (BRENDA: 36 organisms, 102 substrates, 175 inhibitors, 130 Km, 92 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
L-TYROSINE	0.0003–1.19	33
TRNATYR	—	25
ATP	0.0004–7	23
TYROSINE	0.002–0.013	5
K+	22–32	4
3-CHLORO-L-TYROSINE	2.04–2.43	2
3-FLUORO-D,L-TYROSINE	0.625–1.3	2
3-IODO-L-TYROSINE	0.13–1.15	2
D-TYROSINE	0.46–14	2
L-3,4-DIHYDROXYPHENYLALANINE	0.56–1.84	2
L-BETA-(5-HYDROXY-2-PYRIDYL)-ALANINE	0.018–0.038	2
TRNACUA	0.0001–0.001	2
TRNATYR(G34C)	0.0007–0.039	2
TRNATYR(WILD-TYPE)	0.0003–0.0014	2
A22G MUTATED TRNATYR TRANSCRIPT	1.6	1

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Tyr) + L-tyrosine + ATP = L-tyrosyl-tRNA(Tyr) + AMP + diphosphate + H(+) (RHEA:10220)

UniProt features (54 total): helix 18, binding site 10, strand 10, sequence conflict 4, sequence variant 3, modified residue 2, mutagenesis site 2, short sequence motif 2, transit peptide 1, chain 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2PID	X-RAY DIFFRACTION	2.2
3ZXI	X-RAY DIFFRACTION	2.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2Z4-F1	87.57	0.71

Functional residue map

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

Ligand- & substrate-binding residues (10): 244–246; 247; 274; 284; 77; 81; 121; 221; 225; 228

Post-translational modifications (2): 355, 367

Mutagenesis-validated functional residues (2):

Position	Phenotype
200	loss of trna ligase activity.
202	mildly decreased trna ligase activity.

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: 186 (showing top): GOBP_AMINO_ACID_ACTIVATION, GOBP_TRNA_METABOLIC_PROCESS, GOBP_MITOCHONDRIAL_TRANSLATION, GOBP_TRANSLATION, chr12p11, WEI_MYCN_TARGETS_WITH_E_BOX, KORKOLA_EMBRYONAL_CARCINOMA_UP, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, DODD_NASOPHARYNGEAL_CARCINOMA_UP, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, REACTOME_MITOCHONDRIAL_TRNA_AMINOACYLATION, GOCC_MITOCHONDRIAL_MATRIX, GAVIN_IL2_RESPONSIVE_FOXP3_TARGETS_DN, GOMF_AMINO_ACID_BINDING

GO Biological Process (5): translation (GO:0006412), tRNA aminoacylation (GO:0043039), mitochondrial tyrosyl-tRNA aminoacylation (GO:0070184), tRNA aminoacylation for protein translation (GO:0006418), tyrosyl-tRNA aminoacylation (GO:0006437)

GO Molecular Function (10): tRNA binding (GO:0000049), RNA binding (GO:0003723), tyrosine-tRNA ligase activity (GO:0004831), ATP binding (GO:0005524), protein homodimerization activity (GO:0042803), L-tyrosine binding (GO:0072545), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), nuclear body (GO:0016604)

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
mitochondrion	2
cytoplasm	2
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
amino acid activation	1
tyrosyl-tRNA aminoacylation	1
tRNA aminoacylation for mitochondrial protein translation	1
translation	1
tRNA aminoacylation	1
tRNA aminoacylation for protein translation	1
RNA binding	1
nucleic acid binding	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
identical protein binding	1
protein dimerization activity	1
amino acid binding	1
carboxylic acid binding	1
cation 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 membrane-bounded organelle	1
intracellular organelle lumen	1
cellular anatomical structure	1
nucleoplasm	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2835 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
YARS2	PUS1	Q9Y606	942
YARS2	WARS2	Q9UGM6	926
YARS2	AARS1	P49588	920
YARS2	WARS1	P23381	914
YARS2	MARS2	Q96GW9	910
YARS2	MARS1	P56192	904
YARS2	PARS2	Q7L3T8	887
YARS2	QARS1	P47897	881
YARS2	LARS2	Q15031	859
YARS2	IARS2	Q9NSE4	856
YARS2	RARS2	Q5T160	853
YARS2	LARS1	Q9P2J5	847
YARS2	NARS2	Q96I59	846
YARS2	EARS2	Q5JPH6	846
YARS2	GARS1	P41250	844

IntAct

155 interactions, top by confidence:

A	B	Type	Score
CDC20	BUB1B	psi-mi:“MI:0914”(association)	0.980
YARS2	HSPD1	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
FAM9B	YARS2	psi-mi:“MI:0915”(physical association)	0.560
YARS2	FAM9B	psi-mi:“MI:0915”(physical association)	0.560
AGTRAP	YARS2	psi-mi:“MI:0915”(physical association)	0.560
ZNF324B	ZNF316	psi-mi:“MI:0914”(association)	0.530
RBM3	PRMT5	psi-mi:“MI:0914”(association)	0.530
CIRBP	PRMT5	psi-mi:“MI:0914”(association)	0.530
NXF1	CASC3	psi-mi:“MI:0914”(association)	0.530
RBMX	PTCD1	psi-mi:“MI:0914”(association)	0.530
DDX28	PTCD1	psi-mi:“MI:0914”(association)	0.530
TRUB2	HSPD1	psi-mi:“MI:0914”(association)	0.530
MRPL2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
ATP5F1D	NDUFB5	psi-mi:“MI:0914”(association)	0.530
CDC20	BUB3	psi-mi:“MI:0914”(association)	0.530
HNRNPA1	PTCD1	psi-mi:“MI:0914”(association)	0.530
IGF2BP3	PTCD1	psi-mi:“MI:0914”(association)	0.530
RBM3	AARS2	psi-mi:“MI:0914”(association)	0.530
MRPL13	GTPBP10	psi-mi:“MI:0914”(association)	0.530
HNRNPU	MRPS11	psi-mi:“MI:0914”(association)	0.530
PRR3	MRPS14	psi-mi:“MI:0914”(association)	0.530

BioGRID (294): FAM9B (Two-hybrid), YARS2 (Affinity Capture-MS), YARS2 (Affinity Capture-MS), YARS2 (Affinity Capture-MS), YARS2 (Affinity Capture-MS), YARS2 (Affinity Capture-MS), YARS2 (Affinity Capture-MS), YARS2 (Affinity Capture-MS), YARS2 (Affinity Capture-MS), ADAM12 (Co-fractionation), YARS2 (Co-fractionation), YARS2 (Co-fractionation), YARS2 (Proximity Label-MS), YARS2 (Proximity Label-MS), YARS2 (Proximity Label-MS)

ESM2 similar proteins: A2ADA5, A4PCD4, A6H611, D3ZDM7, F6PHZ6, O75344, P04053, P09838, P17256, P36195, P47823, P55345, Q01992, Q03426, Q08602, Q0V8R7, Q13144, Q1L8I0, Q3MIT2, Q4KM92, Q4QQT0, Q5CZL1, Q5E9Z1, Q5I0L3, Q5M7T9, Q5M934, Q5RFE6, Q5XGM5, Q64350, Q6GQ53, Q7L3T8, Q80W22, Q86YJ6, Q8BYL4, Q8C0D0, Q8CHW4, Q8N0Z8, Q8WWH5, Q91XW8, Q92089

Diamond homologs: A0KFT8, A1JNV3, A2RC49, A2RIB1, A4TIS1, A4VYU1, A5FMI1, A5UUZ9, A5VHU6, A6GW04, A6KZL8, A6LGF1, A7FHM0, A7NK64, A8AZI5, A9QZ95, B1I9G6, B1JJR1, B2IN18, B2K5H0, B2RHN4, B3ERY6, B4U045, B5E3A7, B5XJ70, B8ZPM2, B9DN75, B9E7E5, C0M6G7, C0MEE0, C1CAS7, C1CH28, C1CN46, C1CU03, C4K4B6, E6ELF6, O74890, P04077, P0DG62, P0DG63

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
QRICH1	“up-regulates quantity by expression”	YARS2	“transcriptional regulation”
ATF4	“up-regulates quantity by expression”	YARS2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 156 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial ribosome-associated quality control	21	23.7×	5e-21
Mitochondrial translation initiation	18	20.9×	4e-17
Mitochondrial translation elongation	18	20.9×	4e-17
Mitochondrial translation	15	18.9×	1e-13
Mitochondrial translation termination	18	18.1×	4e-16
Translation	16	9.1×	1e-09
Processing of Capped Intron-Containing Pre-mRNA	9	6.8×	4e-04
mRNA Splicing - Major Pathway	10	5.0×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial large ribosomal subunit assembly	8	57.0×	1e-10
mitochondrial translation	20	25.0×	6e-20
regulation of alternative mRNA splicing, via spliceosome	6	10.5×	3e-03
RNA processing	6	9.4×	4e-03
translation	12	8.9×	3e-06
mRNA splicing, via spliceosome	10	6.6×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	9
Uncertain significance	157
Likely benign	123
Benign	11

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
102433	NM_001040436.3(YARS2):c.137G>A (p.Gly46Asp)	Pathogenic
102434	NM_001040436.3(YARS2):c.572G>A (p.Gly191Asp)	Pathogenic
102435	NM_001040436.3(YARS2):c.1078C>T (p.Arg360Ter)	Pathogenic
102436	NM_001040436.3(YARS2):c.1303A>G (p.Ser435Gly)	Pathogenic
2015119	NM_001040436.3(YARS2):c.572dup (p.His192fs)	Pathogenic
2017077	NM_001040436.3(YARS2):c.330_331del (p.Leu111fs)	Pathogenic
2090877	NM_001040436.3(YARS2):c.530dup (p.Tyr177Ter)	Pathogenic
209208	NM_001040436.3(YARS2):c.359dup (p.Asp121fs)	Pathogenic
2105074	NM_001040436.3(YARS2):c.379A>T (p.Lys127Ter)	Pathogenic
2128187	NM_001040436.3(YARS2):c.662del (p.Tyr221fs)	Pathogenic
2194223	NM_001040436.3(YARS2):c.709G>T (p.Gly237Ter)	Pathogenic
2751467	NM_001040436.3(YARS2):c.208_209insT (p.Ala70fs)	Pathogenic
2961890	NM_001040436.3(YARS2):c.382del (p.Glu128fs)	Pathogenic
3001537	NM_001040436.3(YARS2):c.113dup (p.Leu38fs)	Pathogenic
423483	NM_001040436.3(YARS2):c.842del (p.Lys281fs)	Pathogenic
426098	NM_001040436.3(YARS2):c.1106G>A (p.Cys369Tyr)	Pathogenic
426099	NM_001040436.3(YARS2):c.1147_1164dup (p.Val383_Glu388dup)	Pathogenic
4711095	NM_001040436.3(YARS2):c.383_395del (p.Glu128fs)	Pathogenic
4716057	NM_001040436.3(YARS2):c.35del (p.Gly12fs)	Pathogenic
4726038	NM_001040436.3(YARS2):c.610dup (p.Val204fs)	Pathogenic
4726450	NM_001040436.3(YARS2):c.304C>T (p.Gln102Ter)	Pathogenic
4770801	NM_001040436.3(YARS2):c.652G>T (p.Glu218Ter)	Pathogenic
4798526	NM_001040436.3(YARS2):c.661dup (p.Tyr221fs)	Pathogenic
559360	NM_001040436.3(YARS2):c.201dup (p.Gly68fs)	Pathogenic
1193664	NM_001040436.3(YARS2):c.553T>C (p.Phe185Leu)	Likely pathogenic
1196760	NM_001040436.3(YARS2):c.789AGA[1] (p.Glu264del)	Likely pathogenic
2067791	NM_001040436.3(YARS2):c.731G>C (p.Gly244Ala)	Likely pathogenic
209209	NM_001040436.3(YARS2):c.751A>G (p.Ile251Val)	Likely pathogenic
215420	NM_001040436.3(YARS2):c.1396A>G (p.Lys466Glu)	Likely pathogenic
215423	NM_001040436.3(YARS2):c.236G>T (p.Gly79Val)	Likely pathogenic

SpliceAI

2305 predictions. Top by Δscore:

Variant	Effect	Δscore
12:32730980:A:AG	acceptor_gain	1.0000
12:32730981:A:G	acceptor_gain	1.0000
12:32731135:G:GG	donor_gain	1.0000
12:32731467:G:GT	donor_gain	1.0000
12:32731468:A:T	donor_gain	1.0000
12:32731478:G:GT	donor_gain	1.0000
12:32731848:TTGTA:T	acceptor_loss	1.0000
12:32731849:TGTA:T	acceptor_loss	1.0000
12:32731850:GTA:G	acceptor_loss	1.0000
12:32731851:TA:T	acceptor_loss	1.0000
12:32731852:AGG:A	acceptor_loss	1.0000
12:32731853:G:GA	acceptor_loss	1.0000
12:32732525:T:A	acceptor_gain	1.0000
12:32733713:A:AG	acceptor_gain	1.0000
12:32733714:G:GT	acceptor_gain	1.0000
12:32733714:GGTC:G	acceptor_gain	1.0000
12:32733714:GGTCC:G	acceptor_gain	1.0000
12:32733804:AGAGG:A	donor_loss	1.0000
12:32733805:GAG:G	donor_gain	1.0000
12:32733806:AGG:A	donor_loss	1.0000
12:32733808:G:C	donor_loss	1.0000
12:32733808:G:GG	donor_gain	1.0000
12:32733809:T:G	donor_loss	1.0000
12:32737100:CTTAG:C	acceptor_loss	1.0000
12:32737102:TAG:T	acceptor_loss	1.0000
12:32737103:A:AG	acceptor_gain	1.0000
12:32737103:AGG:A	acceptor_loss	1.0000
12:32737104:G:GG	acceptor_gain	1.0000
12:32737157:ACAAG:A	donor_loss	1.0000
12:32737158:CAAGG:C	donor_loss	1.0000

AlphaMissense

3082 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:32747218:A:G	W474R	0.998
12:32747218:A:T	W474R	0.998
12:32749974:A:G	C413R	0.997
12:32750725:G:T	A366D	0.997
12:32747337:A:T	V434D	0.996
12:32750752:A:T	V357D	0.995
12:32747216:C:A	W474C	0.994
12:32747216:C:G	W474C	0.994
12:32747327:A:C	N437K	0.994
12:32747327:A:T	N437K	0.994
12:32747352:A:T	I429K	0.994
12:32750773:G:T	A350E	0.994
12:32747244:C:T	G465E	0.993
12:32755192:T:A	D228V	0.993
12:32747352:A:C	I429R	0.992
12:32749972:G:C	C413W	0.992
12:32755192:T:G	D228A	0.992
12:32747253:A:G	L462P	0.990
12:32747260:A:G	S460P	0.990
12:32750869:A:G	L318P	0.990
12:32753965:A:C	F300L	0.990
12:32753965:A:T	F300L	0.990
12:32753967:A:G	F300L	0.990
12:32747295:A:G	L448S	0.989
12:32750750:G:C	H358D	0.989
12:32755193:C:G	D228H	0.989
12:32753950:G:C	F305L	0.988
12:32753950:G:T	F305L	0.988
12:32753952:A:G	F305L	0.988
12:32755161:G:C	C238W	0.988

dbSNP variants (sampled 300 via entrez): RS1000188572 (12:32754411 T>C), RS1000722577 (12:32756461 C>T), RS1000731028 (12:32748801 G>GGGA), RS1000898175 (12:32757687 G>C), RS1001101195 (12:32749020 CTGAT>C), RS1001118663 (12:32751755 C>T), RS1001511996 (12:32749130 A>C), RS1001577044 (12:32750892 A>T), RS1001625302 (12:32748712 T>G), RS1001774682 (12:32756995 A>T), RS1001918963 (12:32752095 G>A), RS1002141969 (12:32754909 T>A), RS1002406452 (12:32746330 A>T), RS1002722152 (12:32746048 G>T), RS1003160963 (12:32750578 A>G)

Disease associations

OMIM: gene MIM:610957 | disease phenotypes: MIM:613561

GenCC curated gene-disease

Disease	Classification	Inheritance
myopathy, lactic acidosis, and sideroblastic anemia 2	Definitive	Autosomal recessive
myopathy, lactic acidosis, and sideroblastic anemia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (3): myopathy, lactic acidosis, and sideroblastic anemia 2 (MONDO:0013307), mitochondrial disease (MONDO:0044970), myopathy, lactic acidosis, and sideroblastic anemia (MONDO:0000863)

Orphanet (2): Mitochondrial myopathy and sideroblastic anemia (Orphanet:2598), Mitochondrial disease (Orphanet:68380)

HPO phenotypes

46 total (30 of 46 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000508	Ptosis
HP:0000639	Nystagmus
HP:0000823	Delayed puberty
HP:0000980	Pallor
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001270	Motor delay
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001639	Hypertrophic cardiomyopathy
HP:0001903	Anemia
HP:0001924	Sideroblastic anemia
HP:0001939	Abnormality of metabolism/homeostasis
HP:0002015	Dysphagia
HP:0002098	Respiratory distress
HP:0002151	Increased circulating lactate concentration
HP:0002240	Hepatomegaly
HP:0002650	Scoliosis
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0002808	Kyphosis
HP:0002910	Elevated circulating hepatic transaminase concentration

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006479_35	Diverticular disease	3.000000e-06
GCST009391_671	Metabolite levels	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009959	diverticular disease
EFO:0009770	leucine measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536101	Myopathy with lactic acidosis and sideroblastic anemia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	affects cotreatment, decreases expression	2
Tunicamycin	decreases expression, increases expression	2
Valproic Acid	affects expression, decreases expression	2
Thapsigargin	decreases expression, increases expression	2
bisphenol F	increases expression	1
alpha phellandrene	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
trichostatin A	affects expression	1
arsenite	increases methylation	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
bisphenol AF	increases expression	1
Vorinostat	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Atrazine	decreases expression	1
Camptothecin	increases expression	1
Deoxyglucose	increases expression	1
Fluorouracil	increases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Quercetin	decreases expression	1
Ribonucleotides	affects binding	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1

Clinical trials (associated diseases)

108 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
NCT03829657	PHASE3	TERMINATED	Phase 3 Clinical Effect Durability of TD-9855 for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure
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
NCT07465198	PHASE2	NOT_YET_RECRUITING	Autologous Stem Cell Therapy in Patients With Multiple System Atrophy
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
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT02315027	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Mesenchymal Stem Cell Therapy in Multiple System Atrophy
NCT03033680	PHASE1/PHASE2	COMPLETED	Establishing 18F-PBR06 PET Imaging as a Viable Pharmacodynamic Endpoint in MSA
NCT06647641	Not specified	RECRUITING	The CurePSP Genetics Program
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy