RARS2

Summary

RARS2 (arginyl-tRNA synthetase 2, mitochondrial, HGNC:21406) is a protein-coding gene on chromosome 6q15, encoding Probable arginine–tRNA ligase, mitochondrial (Q5T160). Catalyzes the attachment of arginine to tRNA(Arg) in a two-step reaction: arginine is first activated by ATP to form Arg-AMP and then transferred to the acceptor end of tRNA(Arg). It is a selective cancer dependency (DepMap: 58.0% of cell lines).

This nuclear gene encodes a protein that localizes to the mitochondria, where it catalyzes the transfer of L-arginine to its cognate tRNA, an important step in translation of mitochondrially-encoded proteins. Defects in this gene are a cause of pontocerebellar hypoplasia type 6 (PCH6). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 57038 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 1,092 total — 70 pathogenic, 118 likely-pathogenic
• Phenotypes (HPO): 42
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 58.0% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_020320

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21406
Approved symbol	RARS2
Name	arginyl-tRNA synthetase 2, mitochondrial
Location	6q15
Locus type	gene with protein product
Status	Approved
Aliases	MGC14993, MGC23778, PRO1992, dJ382I10.6, DALRD2
Ensembl gene	ENSG00000146282
Ensembl biotype	protein_coding
OMIM	611524
Entrez	57038

Gene structure

Transcript identifiers

Ensembl transcripts: 59 — 20 protein_coding, 20 nonsense_mediated_decay, 18 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000369536, ENST00000451155, ENST00000493269, ENST00000497828, ENST00000684790, ENST00000685069, ENST00000685219, ENST00000685336, ENST00000685376, ENST00000685408, ENST00000685701, ENST00000685881, ENST00000686142, ENST00000686154, ENST00000686196, ENST00000686284, ENST00000686371, ENST00000686407, ENST00000686857, ENST00000686988, ENST00000687078, ENST00000687090, ENST00000687437, ENST00000687579, ENST00000687586, ENST00000687729, ENST00000687909, ENST00000688106, ENST00000688391, ENST00000688532, ENST00000688808, ENST00000688842, ENST00000689174, ENST00000689206, ENST00000689561, ENST00000689594, ENST00000689952, ENST00000690205, ENST00000690555, ENST00000690622, ENST00000690705, ENST00000690884, ENST00000691205, ENST00000691238, ENST00000691259, ENST00000691533, ENST00000691634, ENST00000691725, ENST00000691815, ENST00000692270, ENST00000692394, ENST00000692684, ENST00000692843, ENST00000692934, ENST00000693327, ENST00000693431, ENST00000693524, ENST00000693605, ENST00000879834

RefSeq mRNA: 9 — MANE Select: NM_020320 NM_001318785, NM_001350505, NM_001350506, NM_001350507, NM_001350508, NM_001350509, NM_001350510, NM_001350511, NM_020320

CCDS: CCDS5011, CCDS93968, CCDS93969, CCDS93970

Canonical transcript exons

ENST00000369536 — 20 exons

Exon	Start	End
ENSE00001016480	87555408	87555505
ENSE00001016482	87564130	87564232
ENSE00001016484	87562702	87562785
ENSE00001016486	87548591	87548646
ENSE00001891200	87513938	87514499
ENSE00001923823	87589922	87589987
ENSE00002447604	87518169	87518264
ENSE00002454445	87521464	87521524
ENSE00002458042	87524557	87524652
ENSE00002461782	87530784	87530942
ENSE00002473707	87529542	87529648
ENSE00002492211	87519583	87519707
ENSE00002500723	87518824	87518891
ENSE00002504980	87520180	87520256
ENSE00002515698	87518630	87518739
ENSE00002536213	87541918	87541994
ENSE00003467029	87569517	87569590
ENSE00003496182	87516806	87516880
ENSE00003517941	87514957	87515020
ENSE00003789625	87545616	87545699

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 96.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.8840 / max 709.1135, expressed in 1816 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74628	43.8840	1816

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	96.33	gold quality
adrenal tissue	UBERON:0018303	95.91	gold quality
tibialis anterior	UBERON:0001385	95.09	gold quality
tibia	UBERON:0000979	95.04	gold quality
cartilage tissue	UBERON:0002418	94.95	gold quality
right adrenal gland cortex	UBERON:0035827	94.83	gold quality
right adrenal gland	UBERON:0001233	94.17	gold quality
skin of hip	UBERON:0001554	94.04	gold quality
left adrenal gland	UBERON:0001234	94.03	gold quality
left adrenal gland cortex	UBERON:0035825	94.00	gold quality
pancreatic ductal cell	CL:0002079	93.94	gold quality
adrenal gland	UBERON:0002369	93.84	gold quality
adrenal cortex	UBERON:0001235	93.66	gold quality
calcaneal tendon	UBERON:0003701	93.46	gold quality
sperm	CL:0000019	93.17	gold quality
decidua	UBERON:0002450	92.91	gold quality
amniotic fluid	UBERON:0000173	92.71	gold quality
upper leg skin	UBERON:0004262	92.13	gold quality
parotid gland	UBERON:0001831	92.11	gold quality
deltoid	UBERON:0001476	92.10	gold quality
parietal pleura	UBERON:0002400	91.91	gold quality
epithelial cell of pancreas	CL:0000083	91.90	gold quality
tendon	UBERON:0000043	91.87	gold quality
gingival epithelium	UBERON:0001949	91.84	gold quality
body of pancreas	UBERON:0001150	91.81	gold quality
stromal cell of endometrium	CL:0002255	91.71	gold quality
rectum	UBERON:0001052	91.55	gold quality
endometrium	UBERON:0001295	91.53	gold quality
body of uterus	UBERON:0009853	91.50	gold quality
smooth muscle tissue	UBERON:0001135	91.47	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.17

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

37 targeting RARS2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-6799-5P	99.14	65.72	2093

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 58.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2, may have a role in pontocerebellar hypoplasia type 6 [case report] (PMID:22086604)
• Molecular investigations of RARS2 disclosed the c.25A>G/p.I9V and the c.1586+3A>T in family A. (PMID:22569581)
• Mutations in the RARS2 promoter are likely to represent a new causal mechanism of pontocerebellar hypoplasia. (PMID:25809939)
• RARS2 gene mutations can cause a metabolic neurodegenerative disease manifesting primarily as early onset epileptic encephalopathies with post-natal microcephaly, without pontocerebellar hypoplasia. (PMID:26970947)
• Characteristic neuroradiological abnormalities of PCH6 such as vermis and cerebellar hypoplasia and progressive pontocerebellar atrophy may be missing in patients with RARS2 mutations (PMID:27769281)
• Whole-exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late. (PMID:32725632)
• Novel RARS2 Variants: Updating the Diagnosis and Pathogenesis of Pontocerebellar Hypoplasia Type 6. (PMID:35468344)
• Clinical and genetic analysis of infants with pontocerebellar hypoplasia type 6 caused by RARS2 variations. (PMID:38009286)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rars2	ENSDARG00000032277
mus_musculus	Rars2	ENSMUSG00000028292
rattus_norvegicus	Rars2	ENSRNOG00000008643
drosophila_melanogaster	ArgRS-m	FBGN0037526

Paralogs (1): RARS1 (ENSG00000113643)

Protein

Protein identifiers

Probable arginine–tRNA ligase, mitochondrial — Q5T160 (reviewed: Q5T160)

Alternative names: Arginyl-tRNA synthetase

All UniProt accessions (27): Q5T160, A0A8I5KP51, A0A8I5KPR3, A0A8I5KPX4, A0A8I5KPZ0, A0A8I5KPZ4, A0A8I5KQK8, A0A8I5KQP4, A0A8I5KQS8, A0A8I5KQV7, A0A8I5KR42, A0A8I5KR81, A0A8I5KRE6, A0A8I5KS21, A0A8I5KS32, A0A8I5KU19, A0A8I5KVK0, A0A8I5KVZ5, A0A8I5KWC6, A0A8I5KWE8, A0A8I5KX97, A0A8I5KXM9, A0A8I5KYL9, A0A8I5QJN6, A0A8I5QJX6, H0UI22, H0Y450

UniProt curated annotations — full annotation on UniProt →

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

Subcellular location. Mitochondrion membrane.

Disease relevance. Pontocerebellar hypoplasia 6 (PCH6) [MIM:611523] A disorder characterized by an abnormally small cerebellum and brainstem, infantile encephalopathy, generalized hypotonia, lethargy and poor feeding. Recurrent apnea, intractable seizures occur early in the course of this condition. 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 (9): NP_001305714, NP_001337434, NP_001337435, NP_001337436, NP_001337437, NP_001337438, NP_001337439, NP_001337440, NP_064716* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001278	Arg-tRNA-ligase	Family
IPR001412	aa-tRNA-synth_I_CS	Conserved_site
IPR008909	DALR_anticod-bd	Domain
IPR009080	tRNAsynth_Ia_anticodon-bd	Homologous_superfamily
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR035684	ArgRS_core	Domain
IPR036695	Arg-tRNA-synth_N_sf	Homologous_superfamily

Pfam: PF00750, PF05746

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Arg) + L-arginine + ATP = L-arginyl-tRNA(Arg) + AMP + diphosphate (RHEA:20301)

UniProt features (32 total): mutagenesis site 12, sequence variant 9, binding site 5, sequence conflict 2, transit peptide 1, chain 1, short sequence motif 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5T160-F1	89.18	0.64

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 (5): 133–135; 144; 322; 326; 350

Post-translational modifications (1): 568

Mutagenesis-validated functional residues (12):

Position	Phenotype
9	no effect on mitochondrial membrane localization.
12	no effect on mitochondrial membrane localization.
241	no effect on mitochondrial membrane localization.
245	no effect on mitochondrial membrane localization.
258	no effect on mitochondrial membrane localization.
283	no effect on mitochondrial membrane localization.
333	no effect on mitochondrial membrane localization.
342	no effect on mitochondrial membrane localization.
404	no effect on mitochondrial membrane localization.
469	no effect on mitochondrial membrane localization.
478	no effect on mitochondrial membrane localization.
530	no effect on mitochondrial membrane localization.

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: 175 (showing top): chr6q15, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_AMINO_ACID_ACTIVATION, PAL_PRMT5_TARGETS_UP, GOBP_TRNA_METABOLIC_PROCESS, GOBP_MITOCHONDRIAL_TRANSLATION, GOBP_TRANSLATION, GOCC_MITOCHONDRIAL_ENVELOPE, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, REACTOME_MITOCHONDRIAL_TRNA_AMINOACYLATION, GOCC_MITOCHONDRIAL_MATRIX, GOMF_LIGASE_ACTIVITY_FORMING_CARBON_OXYGEN_BONDS, GOMF_ADENYL_NUCLEOTIDE_BINDING, GOCC_ORGANELLE_ENVELOPE, WAKABAYASHI_ADIPOGENESIS_PPARG_BOUND_8D

GO Biological Process (6): tRNA aminoacylation for protein translation (GO:0006418), arginyl-tRNA aminoacylation (GO:0006420), mitochondrial translation (GO:0032543), tRNA metabolic process (GO:0006399), translation (GO:0006412), gene expression (GO:0010467)

GO Molecular Function (7): RNA binding (GO:0003723), arginine-tRNA ligase activity (GO:0004814), 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 (5): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), mitochondrial membrane (GO:0031966), cytoplasm (GO:0005737), membrane (GO:0016020)

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	3
translation	2
macromolecule biosynthetic process	2
cellular anatomical structure	2
tRNA aminoacylation	1
tRNA aminoacylation for protein translation	1
mitochondrial gene expression	1
RNA metabolic process	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
protein metabolic process	1
protein biosynthetic process	1
nucleic acid 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
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
mitochondrial envelope	1
organelle membrane	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2581 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RARS2	QARS1	P47897	998
RARS2	KARS1	Q15046	998
RARS2	EPRS1	P07814	988
RARS2	LARS2	Q15031	987
RARS2	LARS1	Q9P2J5	986
RARS2	IARS1	P41252	982
RARS2	IARS2	Q9NSE4	974
RARS2	MARS2	Q96GW9	960
RARS2	MARS1	P56192	955
RARS2	TSEN54	Q7Z6J9	952
RARS2	SARS1	P49591	930
RARS2	M0R2C6	M0R2C6	929
RARS2	SARS2	Q9NP81	929
RARS2	AARS1	P49588	899
RARS2	VARS2	Q5ST30	884

IntAct

100 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
COMT	RARS2	psi-mi:“MI:0915”(physical association)	0.560
TGM2	RARS2	psi-mi:“MI:0915”(physical association)	0.560
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
NPY2R	RTL8C	psi-mi:“MI:0914”(association)	0.530
TNFSF8	LGALS8	psi-mi:“MI:0914”(association)	0.530
TMEM184A	SLC33A1	psi-mi:“MI:0914”(association)	0.530
RARS2	HSPD1	psi-mi:“MI:0915”(physical association)	0.400
EDNRB	RARS2	psi-mi:“MI:0915”(physical association)	0.400
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
Rhoa	CLK2	psi-mi:“MI:0914”(association)	0.350
NS1	ESYT2	psi-mi:“MI:0914”(association)	0.350
M2	ESYT2	psi-mi:“MI:0914”(association)	0.350
BCL2L14		psi-mi:“MI:0914”(association)	0.350
NT5C3A	VWA8	psi-mi:“MI:0914”(association)	0.350
P2RY6	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC15A3		psi-mi:“MI:0914”(association)	0.350
RARS2	PCCA	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
AKAP10	HAX1	psi-mi:“MI:0914”(association)	0.350
rep	NPEPPSL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (118): RARS2 (Affinity Capture-MS), CPS1 (Affinity Capture-MS), ATP12A (Affinity Capture-MS), GFM2 (Affinity Capture-MS), PITRM1 (Affinity Capture-MS), GLS (Affinity Capture-MS), PDPR (Affinity Capture-MS), PCCA (Affinity Capture-MS), PREPL (Affinity Capture-MS), PLXDC2 (Affinity Capture-MS), MCCC1 (Affinity Capture-MS), CLN3 (Affinity Capture-MS), ARL8A (Affinity Capture-MS), AARS2 (Affinity Capture-MS), NSDHL (Affinity Capture-MS)

ESM2 similar proteins: A0A1D6LAG9, A2C016, A6ZMR9, A7YW98, B3LM95, C7GRE4, C8ZF72, F4IPY2, O14000, O14160, O23247, O74742, O74781, O74858, O75005, O94710, P07806, P11325, P13503, P21894, P22438, P32874, P38714, P48526, P49696, Q05506, Q09828, Q0P5H7, Q3U186, Q493S3, Q4R646, Q54CE4, Q54MZ8, Q558Z0, Q5REH3, Q5T160, Q5UP36, Q5UQ59, Q5ZKA2, Q6DJ95

Diamond homologs: A2RGX5, A2RNI8, A4VYA3, A4W4J9, A5I0R5, A5N8F9, A5VL03, A6LS73, A6TNX2, A7FSW7, A7GCB9, A9WEH7, B1I9E7, B1IIE6, B1KYT1, B1MZ82, B1XPX8, B1YFI1, B2G8D8, B2GDD7, B2IMZ8, B2UW74, B2VJB6, B3PKE3, B5E387, B5XJ77, B8CWA9, B8G4J9, B8ZPK2, B9DW76, B9E1W5, B9LGY2, C0MAS8, C0MGC8, C1CAQ7, C1CH08, C1CN25, C1CTY4, C1FK28, C3KSZ0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 122 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.

GO biological processes:

GO term	Partners	Fold	FDR
G protein-coupled receptor signaling pathway	14	4.7×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1092 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	70
Likely pathogenic	118
Uncertain significance	220
Likely benign	472
Benign	52

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067194	NM_020320.5(RARS2):c.297+1G>A	Pathogenic
1068541	NM_020320.5(RARS2):c.1376dup (p.Gly460fs)	Pathogenic
1068811	NM_020320.5(RARS2):c.184C>T (p.Gln62Ter)	Pathogenic
1070700	NM_020320.5(RARS2):c.259_262dup (p.Val88fs)	Pathogenic
1070705	NM_020320.5(RARS2):c.3G>A (p.Met1Ile)	Pathogenic
1073705	NM_020320.5(RARS2):c.670C>T (p.Gln224Ter)	Pathogenic
1075015	NM_020320.5(RARS2):c.297+1del	Pathogenic
1075072	NC_000006.11:g.(?88273838)(88273960_?)del	Pathogenic
1375780	NM_020320.5(RARS2):c.996del (p.Arg333fs)	Pathogenic
1427423	NM_020320.5(RARS2):c.1432G>T (p.Gly478Ter)	Pathogenic
1429786	NM_020320.5(RARS2):c.1570del (p.Tyr524fs)	Pathogenic
1450145	NM_020320.5(RARS2):c.3G>T (p.Met1Ile)	Pathogenic
1451754	NM_020320.5(RARS2):c.622C>T (p.Gln208Ter)	Pathogenic
1453187	NM_020320.5(RARS2):c.68del (p.Asn23fs)	Pathogenic
1454806	NM_020320.5(RARS2):c.722G>A (p.Trp241Ter)	Pathogenic
1455488	NM_020320.5(RARS2):c.2T>A (p.Met1Lys)	Pathogenic
1455810	NC_000006.11:g.(?88279225)(88279318_?)del	Pathogenic
1457540	NC_000006.11:g.(?88182712)(88299760_?)del	Pathogenic
1457649	NM_020320.5(RARS2):c.940dup (p.Met314fs)	Pathogenic
1460357	NC_000006.11:g.(?88239250)(88251722_?)del	Pathogenic
1460368	NC_000006.11:g.(?88239250)(88240670_?)del	Pathogenic
1686120	NM_020320.5(RARS2):c.422A>G (p.His141Arg)	Pathogenic
1995416	NM_020320.5(RARS2):c.809C>G (p.Ser270Ter)	Pathogenic
2000846	NM_020320.5(RARS2):c.395+1del	Pathogenic
2010897	NM_020320.5(RARS2):c.1274del (p.Glu425fs)	Pathogenic
2021409	NM_020320.5(RARS2):c.638del (p.Ala213fs)	Pathogenic
2033793	NM_020320.5(RARS2):c.649A>T (p.Lys217Ter)	Pathogenic
2075125	NM_020320.5(RARS2):c.1405delinsTCGCCCGATGTGTAGGAAGAGGCAGATAAAGAATATTGAGGCGCCATTGGCGTGAAGGTAGCGGATGATTCAGCCATAATTTACGTCTCGAGTGATGTGGGCGATTGATGAAAAGGCGGTTGAGGCGTCTGGTGAGTAGTGCATGGCTAGGAATAGTCCTGTGGTGATTTGGAGGATCAGGCAG (p.Arg469delinsSerProAspValTer)	Pathogenic
2231814	NM_020320.5(RARS2):c.1163del (p.Gly388fs)	Pathogenic
2426535	NC_000006.11:g.(?88226514)(88231252_?)del	Pathogenic

SpliceAI

3691 predictions. Top by Δscore:

Variant	Effect	Δscore
6:87518266:T:C	acceptor_gain	1.0000
6:87518889:TTG:T	acceptor_gain	1.0000
6:87518892:C:CC	acceptor_gain	1.0000
6:87519581:A:AC	donor_gain	1.0000
6:87519582:C:CC	donor_gain	1.0000
6:87519582:CT:C	donor_gain	1.0000
6:87519587:A:AC	donor_gain	1.0000
6:87519588:A:C	donor_gain	1.0000
6:87529516:A:AC	donor_gain	1.0000
6:87529517:C:CC	donor_gain	1.0000
6:87529569:T:A	donor_gain	1.0000
6:87529579:TTAAG:T	donor_gain	1.0000
6:87529647:CG:C	acceptor_gain	1.0000
6:87529649:C:CC	acceptor_gain	1.0000
6:87529660:C:CT	acceptor_gain	1.0000
6:87529661:A:T	acceptor_gain	1.0000
6:87530778:CAATA:C	donor_loss	1.0000
6:87530779:AATAC:A	donor_loss	1.0000
6:87530781:TACCT:T	donor_loss	1.0000
6:87530782:A:AG	donor_loss	1.0000
6:87530786:TGTAA:T	donor_gain	1.0000
6:87530938:TAAAC:T	acceptor_gain	1.0000
6:87530939:AAAC:A	acceptor_gain	1.0000
6:87530940:AAC:A	acceptor_gain	1.0000
6:87530942:CCTA:C	acceptor_loss	1.0000
6:87530943:CTAAA:C	acceptor_loss	1.0000
6:87530944:T:G	acceptor_loss	1.0000
6:87542009:C:CT	acceptor_gain	1.0000
6:87542009:C:T	acceptor_gain	1.0000
6:87555502:CTGT:C	acceptor_gain	1.0000

AlphaMissense

3791 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:87521501:C:G	R333P	0.995
6:87548646:A:C	S132R	0.995
6:87548646:A:T	S132R	0.995
6:87555409:T:G	S132R	0.995
6:87530811:G:C	S248R	0.992
6:87530811:G:T	S248R	0.992
6:87530813:T:G	S248R	0.992
6:87519689:A:C	F377L	0.988
6:87519689:A:T	F377L	0.988
6:87519691:A:G	F377L	0.988
6:87545634:C:G	D173H	0.988
6:87545644:A:C	N169K	0.988
6:87545644:A:T	N169K	0.988
6:87548629:T:A	K138I	0.988
6:87545617:A:C	F178L	0.987
6:87545617:A:T	F178L	0.987
6:87545619:A:G	F178L	0.987
6:87545699:C:T	G151E	0.986
6:87530821:C:G	R245P	0.983
6:87545681:A:G	L157P	0.983
6:87545699:C:A	G151V	0.983
6:87548606:G:T	R146S	0.983
6:87521514:C:G	A329P	0.982
6:87545633:T:G	D173A	0.982
6:87548628:T:A	K138N	0.982
6:87548628:T:G	K138N	0.982
6:87541994:C:T	G179D	0.981
6:87545631:A:G	W174R	0.981
6:87545631:A:T	W174R	0.981
6:87555410:G:C	F131L	0.981

dbSNP variants (sampled 300 via entrez): RS1000022182 (6:87514595 A>G), RS1000024592 (6:87515076 A>T), RS1000037701 (6:87556087 T>C), RS1000051753 (6:87521822 C>T), RS1000095647 (6:87562387 A>G), RS1000101085 (6:87513760 T>G), RS1000121977 (6:87520493 A>G), RS1000125028 (6:87521605 C>A), RS1000163824 (6:87549705 T>C), RS1000192297 (6:87550323 G>A), RS1000240627 (6:87514922 T>C), RS1000268748 (6:87556321 T>C), RS1000347866 (6:87585398 T>C), RS1000369324 (6:87575264 CA>C), RS1000430516 (6:87590091 C>T)

Disease associations

OMIM: gene MIM:611524 | disease phenotypes: MIM:611523, MIM:607596, MIM:213000

GenCC curated gene-disease

Disease	Classification	Inheritance
pontocerebellar hypoplasia type 6	Definitive	Autosomal recessive
complex neurodevelopmental disorder	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (5): pontocerebellar hypoplasia type 6 (MONDO:0012683), pontocerebellar hypoplasia (MONDO:0020135), mitochondrial disease (MONDO:0044970), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (5): Pontocerebellar hypoplasia type 6 (Orphanet:166073), Non-syndromic pontocerebellar hypoplasia (Orphanet:98523), Mitochondrial disease (Orphanet:68380), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000189	Narrow palate
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000341	Narrow forehead
HP:0000426	Prominent nasal bridge
HP:0000490	Deeply set eye
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001320	Cerebellar vermis hypoplasia
HP:0001321	Cerebellar hypoplasia
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0002020	Gastroesophageal reflux
HP:0002033	Poor suck
HP:0002059	Cerebral atrophy
HP:0002061	Lower limb spasticity
HP:0002104	Apnea
HP:0002120	Cerebral cortical atrophy
HP:0002151	Increased circulating lactate concentration
HP:0002197	Generalized-onset seizure
HP:0002421	Poor head control
HP:0002490	Increased CSF lactate
HP:0003577	Congenital onset
HP:0003676	Progressive

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001762_245	Obesity-related traits	4.000000e-06
GCST001762_760	Obesity-related traits	4.000000e-06
GCST004224_8	Coronary atherosclerosis (increased number of diseased vessels) (traffic exposure interaction)	1.000000e-06
GCST006633_14	Initial alcohol sensitivity	3.000000e-06
GCST009524_289	Household income (MTAG)	5.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005106	body composition measurement
EFO:0007908	traffic air pollution measurement
EFO:0007938	coronary atherosclerosis measurement
EFO:0009695	household income

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
C562568	Cerebellar Hypoplasia (supp.)
C580383	Pontocerebellar Hypoplasia (supp.)
C548074	Pontocerebellar Hypoplasia Type 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067361 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.48	Kd	3.279	nM	CHEMBL5653589
8.48	ED50	3.279	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149195: Binding affinity to human RARS2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0033	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, affects expression	3
sodium arsenite	decreases expression, increases expression	2
Acetaminophen	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
glycidyl methacrylate	decreases expression	1
beta-lapachone	increases expression	1
vanadyl sulfate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Lipopolysaccharides	decreases expression, affects cotreatment	1
Plant Extracts	affects cotreatment, increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652237	Binding	Binding affinity to human RARS2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

105 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
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
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
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
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
NCT00786539	Not specified	COMPLETED	Mitochondria Inborn Errors of Metabolism and ANT Defects in Mitochondria Diseases
NCT00829270	Not specified	COMPLETED	Economic and Medical Evaluation of the Whole Mitochondrial DNA Screening by Surveyor and Mitochips Techniques
NCT00831948	Not specified	UNKNOWN	Identification of Large-Scale Mutations of POLG Gene by QMPSF in Patients With Mitochondrial DNA Instability.