VARS1

Summary

VARS1 (valyl-tRNA synthetase 1, HGNC:12651) is a protein-coding gene on chromosome 6p21.33, encoding Valine–tRNA ligase (P26640). Catalyzes the attachment of valine to tRNA(Val). It is a common-essential gene (DepMap: required in 99.5% of cancer cell lines).

Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. The protein encoded by this gene belongs to class-I aminoacyl-tRNA synthetase family and is located in the class III region of the major histocompatibility complex.

Source: NCBI Gene 7407 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 61
• Clinical variants (ClinVar): 846 total — 29 pathogenic, 32 likely-pathogenic
• Phenotypes (HPO): 60
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_006295

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12651
Approved symbol	VARS1
Name	valyl-tRNA synthetase 1
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000204394
Ensembl biotype	protein_coding
OMIM	192150
Entrez	7407

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 18 protein_coding, 8 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000375663, ENST00000428445, ENST00000440048, ENST00000459667, ENST00000461328, ENST00000461874, ENST00000463184, ENST00000470953, ENST00000474643, ENST00000479051, ENST00000482996, ENST00000483275, ENST00000489979, ENST00000495010, ENST00000851848, ENST00000851849, ENST00000851850, ENST00000851851, ENST00000925768, ENST00000925769, ENST00000925770, ENST00000925771, ENST00000925772, ENST00000925773, ENST00000925774, ENST00000925775, ENST00000925776, ENST00000941400, ENST00000941401

RefSeq mRNA: 1 — MANE Select: NM_006295 NM_006295

CCDS: CCDS34412

Canonical transcript exons

ENST00000211402 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 96.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 59.7546 / max 1063.2768, expressed in 1820 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72826	51.4997	1819
72822	1.4461	777
72830	1.1715	594
72831	1.0844	581
72824	0.9789	580
72829	0.9675	443
72825	0.8475	379
72823	0.7778	428
72832	0.3761	131
72828	0.3107	94

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	96.41	gold quality
left testis	UBERON:0004533	96.35	gold quality
testis	UBERON:0000473	96.00	gold quality
cortical plate	UBERON:0005343	95.79	gold quality
islet of Langerhans	UBERON:0000006	95.38	gold quality
pituitary gland	UBERON:0000007	94.78	gold quality
ganglionic eminence	UBERON:0004023	94.42	gold quality
vermiform appendix	UBERON:0001154	94.33	gold quality
adenohypophysis	UBERON:0002196	94.18	gold quality
stromal cell of endometrium	CL:0002255	94.06	gold quality
gastrocnemius	UBERON:0001388	93.93	gold quality
pancreas	UBERON:0001264	93.83	gold quality
muscle tissue	UBERON:0002385	93.70	gold quality
skeletal muscle tissue	UBERON:0001134	93.52	gold quality
body of pancreas	UBERON:0001150	93.30	gold quality
muscle of leg	UBERON:0001383	93.20	gold quality
smooth muscle tissue	UBERON:0001135	93.00	gold quality
left uterine tube	UBERON:0001303	92.98	gold quality
spleen	UBERON:0002106	92.98	gold quality
mucosa of transverse colon	UBERON:0004991	92.96	gold quality
esophagus mucosa	UBERON:0002469	92.92	gold quality
lower esophagus mucosa	UBERON:0035834	92.85	gold quality
skin of leg	UBERON:0001511	92.84	gold quality
zone of skin	UBERON:0000014	92.56	gold quality
lymph node	UBERON:0000029	92.54	gold quality
tonsil	UBERON:0002372	92.52	gold quality
bone marrow cell	CL:0002092	92.15	gold quality
skin of abdomen	UBERON:0001416	92.08	gold quality
body of uterus	UBERON:0009853	92.08	gold quality
esophagus	UBERON:0001043	91.91	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.28
E-MTAB-6524	no	21.30

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1H4, QRICH1

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 6)

• The first three-dimensional structure of the the valyl-tRNA synthetase/elongation factor-1H complex as calculated from electron microscopic images of negatively stained samples of the human ValRS/EF-1H complex was obtained. (PMID:16229838)
• Our study describes the phenotype associated with recessive VARS mutations and further functional delineation of the pathogenicity of novel variants identified, which widens the clinical and genetic spectrum of patients with progressive microcephaly (PMID:29691655)
• Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes. (PMID:30755602)
• Effects of PPM1K rs1440581 and rs7678928 on serum branched-chain amino acid levels and risk of cardiovascular disease. (PMID:34382495)
• High expression of VARS promotes the growth of multiple myeloma cells by causing imbalance in valine metabolism. (PMID:37587064)
• Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma. (PMID:38849541)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	vars1	ENSDARG00000044575
mus_musculus	Vars1	ENSMUSG00000007029
rattus_norvegicus	Vars1	ENSRNOG00000000867
drosophila_melanogaster	ValRS	FBGN0027079
caenorhabditis_elegans	glp-4	WBGENE00006936

Paralogs (7): LARS2 (ENSG00000011376), IARS2 (ENSG00000067704), LARS1 (ENSG00000133706), VARS2 (ENSG00000137411), MARS1 (ENSG00000166986), IARS1 (ENSG00000196305), MARS2 (ENSG00000247626)

Protein

Protein identifiers

Valine–tRNA ligase — P26640 (reviewed: P26640)

Alternative names: Protein G7a, Valyl-tRNA synthetase

All UniProt accessions (4): P26640, A0A024RCN6, A2ABF4, H0Y426

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the attachment of valine to tRNA(Val).

Subunit / interactions. Forms high-molecular-mass aggregates with elongation factor 1.

Disease relevance. Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA) [MIM:617802] An autosomal recessive neurodevelopmental disorder characterized by severe developmental delay, intellectual disability, severe microcephaly, and cortical atrophy. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. Can be regulated by protein kinase C-dependent phosphorylation.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P26640-1	1	yes
P26640-2	2

RefSeq proteins (1): NP_006286* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001412	aa-tRNA-synth_I_CS	Conserved_site
IPR002300	aa-tRNA-synth_Ia	Domain
IPR002303	Valyl-tRNA_ligase	Family
IPR004046	GST_C	Domain
IPR009008	Val/Leu/Ile-tRNA-synth_edit	Homologous_superfamily
IPR009080	tRNAsynth_Ia_anticodon-bd	Homologous_superfamily
IPR010987	Glutathione-S-Trfase_C-like	Domain
IPR013155	M/V/L/I-tRNA-synth_anticd-bd	Domain
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR033705	Anticodon_Ia_Val	Domain
IPR036282	Glutathione-S-Trfase_C_sf	Homologous_superfamily
IPR037118	Val-tRNA_synth_C_sf	Homologous_superfamily

Pfam: PF00043, PF00133, PF08264

Enzyme classification (BRENDA):

• EC 6.1.1.9 — valine-tRNA ligase (BRENDA: 22 organisms, 56 substrates, 16 inhibitors, 72 Km, 31 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
TRNAVAL	0.0001–0.042	19
L-VALINE	0.0019–0.1926	16
ATP	0.029–13.4	13
VALINE	0.001–0.1	8
L-VALYL-TRNAVAL	0.0002–0.001	2
DL-2-AMINO-3-CHLOROBUTYRATE	0.33	1
DL-2-AMINOBUTYRATE	3.7	1
DL-ALLO-2-AMINO-3-CHLOROBUTYRATE	1	1
DL-THREONINE	12	1
L-ISOLEUCINE	1.9	1
L-NORVALINE	14	1
L-THREONINE	0.3	1
TRNAVAL(GAC)	0.0006	1
TRNAVAL(UAC)	0.0021	1
TRNAVAL(UAC-2)	0.0011	1

Catalyzed reactions (Rhea), 1 shown:

• tRNA(Val) + L-valine + ATP = L-valyl-tRNA(Val) + AMP + diphosphate (RHEA:10704)

UniProt features (29 total): sequence variant 7, sequence conflict 6, modified residue 4, splice variant 3, short sequence motif 2, compositionally biased region 2, initiator methionine 1, chain 1, domain 1, region of interest 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P26640-F1	88.12	0.65

Functional residue map

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

Ligand- & substrate-binding residues (1): 865

Post-translational modifications (4): 437, 527, 645, 2

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-379716	Cytosolic tRNA aminoacylation
R-HSA-379724	tRNA Aminoacylation
R-HSA-392499	Metabolism of proteins
R-HSA-72766	Translation

MSigDB gene sets: 403 (showing top): GOBP_AMINO_ACID_ACTIVATION, GOBP_TRNA_METABOLIC_PROCESS, PATIL_LIVER_CANCER, GOBP_TRANSLATION, SCHUHMACHER_MYC_TARGETS_UP, CEBALLOS_TARGETS_OF_TP53_AND_MYC_DN, KLEIN_PRIMARY_EFFUSION_LYMPHOMA_UP, MORF_PRKDC, MODULE_110, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, IK2_01, GOBP_REGULATION_OF_TRANSLATIONAL_FIDELITY, REACTOME_MITOCHONDRIAL_TRNA_AMINOACYLATION, MORF_AATF, IVANOVA_HEMATOPOIESIS_EARLY_PROGENITOR

GO Biological Process (4): tRNA aminoacylation for protein translation (GO:0006418), valyl-tRNA aminoacylation (GO:0006438), translation (GO:0006412), aminoacyl-tRNA metabolism involved in translational fidelity (GO:0106074)

GO Molecular Function (7): aminoacyl-tRNA deacylase activity (GO:0002161), valine-tRNA ligase activity (GO:0004832), 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): endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229)

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
cellular anatomical structure	4
sperm flagellum	3
catalytic activity, acting on a tRNA	2
cytoplasm	2
translation	1
tRNA aminoacylation	1
tRNA aminoacylation for protein translation	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
tRNA metabolic process	1
regulation of translational fidelity	1
carboxylic ester hydrolase activity	1
aminoacyl-tRNA metabolism involved in translational fidelity	1
deacylase activity	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ligase activity, forming carbon-oxygen bonds	1
binding	1
catalytic activity	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

5353 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VARS1	VWA7	Q9Y334	969
VARS1	RARS2	Q5T160	883
VARS1	WARS2	Q9UGM6	877
VARS1	WARS1	P23381	869
VARS1	KARS1	Q15046	863
VARS1	LARS1	Q9P2J5	861
VARS1	TARS2	Q9BW92	851
VARS1	TARS3	A2RTX5	845
VARS1	PARS2	Q7L3T8	845
VARS1	TARS1	P26639	845
VARS1	MARS2	Q96GW9	844
VARS1	CARS2	Q9HA77	842
VARS1	QARS1	P47897	841
VARS1	AARS1	P49588	837
VARS1	EARS2	Q5JPH6	815

IntAct

154 interactions, top by confidence:

A	B	Type	Score
FOS	JUN	psi-mi:“MI:0914”(association)	0.980
EEF1G	EEF1B2	psi-mi:“MI:0914”(association)	0.890
EEF1A2	EEF1B2	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CALCOCO2	VARS1	psi-mi:“MI:0915”(physical association)	0.560
VARS1	CAMK2B	psi-mi:“MI:0915”(physical association)	0.560
VARS1	CAMK2A	psi-mi:“MI:0915”(physical association)	0.560
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
MLLT6	RGPD8	psi-mi:“MI:0914”(association)	0.530
EEF1G	INPPL1	psi-mi:“MI:0914”(association)	0.530
FOSL2	ZZEF1	psi-mi:“MI:0914”(association)	0.530
EEF1A1	ZPR1	psi-mi:“MI:0914”(association)	0.530
CORO1A	VARS1	psi-mi:“MI:0914”(association)	0.530
ABTB1	VARS1	psi-mi:“MI:0914”(association)	0.530
NME1	NME2P1	psi-mi:“MI:0914”(association)	0.530
FOS	YEATS4	psi-mi:“MI:0914”(association)	0.530

BioGRID (341): CALCOCO2 (Two-hybrid), VARS (Affinity Capture-MS), VARS (Affinity Capture-MS), VARS (Affinity Capture-MS), VARS (Affinity Capture-MS), VARS (Affinity Capture-MS), VARS (Affinity Capture-MS), VARS (Affinity Capture-MS), EEF1G (Co-fractionation), FAM98B (Co-fractionation), TP53RK (Co-fractionation), VARS (Co-fractionation), VARS (Co-fractionation), VARS (Co-fractionation), VARS (Co-fractionation)

ESM2 similar proteins: A0A1D6LAG9, A6H7E1, D3ZX08, F4IPY2, F4KE63, O14000, O75879, P26640, P49696, P56192, Q04462, Q0IZQ2, Q0P499, Q14CH7, Q15031, Q2KIF8, Q2T9L8, Q3U2A8, Q499X9, Q4R646, Q5JPH6, Q5P9M8, Q5RCH4, Q5RDP4, Q5ST30, Q5TM74, Q5ZKA2, Q66JG3, Q68FL6, Q6DJ95, Q6GQJ7, Q6MG21, Q6PA41, Q767M3, Q7T0Z0, Q8BIJ6, Q8BYM8, Q8RXK8, Q8VDC0, Q90YI3

Diamond homologs: A0A1U8QXK4, A0A6J4B5J2, A2Q127, O04487, O74830, P12261, P26640, P26641, P26642, P29547, P29694, P34715, P36008, P40921, P49696, P54412, P9WEZ8, Q00717, Q04462, Q29387, Q3SZV3, Q4R7H5, Q52828, Q5Z627, Q68FR6, Q6PE25, Q6YW46, Q90YC0, Q91375, Q9D8N0, Q9FUM1, Q9FVT2, Q9NJH0, Q9Z1Q9, Q9ZRI7, S0EHD0, W7MMJ0, A3N2F0, A4G1V2, A5ITI8

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
QRICH1	“up-regulates quantity by expression”	VARS1	“transcriptional regulation”
VARS1	“down-regulates quantity”	tRNA(Val)	“chemical modification”
VARS1	“down-regulates quantity”	valine	“chemical modification”
VARS1	“down-regulates quantity”	ATP(4-)	“chemical modification”
VARS1	“up-regulates quantity”	diphosphate(3-)	“chemical modification”
VARS1	“up-regulates quantity”	AMP	“chemical modification”
VARS1	“up-regulates quantity”	Val-tRNA(Val)	“chemical modification”
VARS1	“up-regulates quantity”	alpha-aminoacyl-tRNA	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 176 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
Ovarian tumor domain proteases	6	13.6×	1e-03
G-protein mediated events	5	13.3×	2e-03
DAG and IP3 signaling	5	12.9×	2e-03
HSF1-dependent transactivation	5	12.9×	2e-03
Degradation of DVL	6	11.6×	1e-03
Eukaryotic Translation Elongation	5	11.3×	3e-03
Opioid Signalling	5	10.8×	3e-03
PLC beta mediated events	5	10.8×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
integrated stress response signaling	5	22.8×	4e-04
positive regulation of miRNA transcription	7	13.2×	3e-04
anatomical structure morphogenesis	9	8.1×	4e-04
response to ethanol	7	6.7×	1e-02
negative regulation of gene expression	10	4.5×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	29
Likely pathogenic	32
Uncertain significance	443
Likely benign	180
Benign	75

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1031626	NM_006295.3(VARS1):c.3646C>T (p.Gln1216Ter)	Pathogenic
1357313	NM_020442.6(VARS2):c.3004C>T (p.Arg1002Ter)	Pathogenic
141424	NM_020442.6(VARS2):c.1045G>A (p.Ala349Thr)	Pathogenic
141427	NM_020442.6(VARS2):c.1010C>T (p.Thr337Ile)	Pathogenic
1420183	NM_020442.6(VARS2):c.2749C>T (p.Arg917Ter)	Pathogenic
1940105	NM_020442.6(VARS2):c.1563G>A (p.Trp521Ter)	Pathogenic
2082700	NM_006295.3(VARS1):c.1251G>A (p.Trp417Ter)	Pathogenic
2272875	NM_020442.6(VARS2):c.1219C>T (p.Arg407Ter)	Pathogenic
2423916	NC_000006.11:g.(?30890861)(30892357_?)del	Pathogenic
2581609	NM_020442.6(VARS2):c.420del (p.Met141fs)	Pathogenic
2784529	NM_020442.6(VARS2):c.571C>T (p.Gln191Ter)	Pathogenic
3251797	NM_006295.3(VARS1):c.1137del (p.Gly380fs)	Pathogenic
3255217	NM_020442.6(VARS2):c.667G>T (p.Glu223Ter)	Pathogenic
3376811	NM_006295.3(VARS1):c.1603del (p.Thr535fs)	Pathogenic
4532026	NM_006295.3(VARS1):c.3463C>T (p.Gln1155Ter)	Pathogenic
4699300	NM_020442.6(VARS2):c.2782C>T (p.Arg928Ter)	Pathogenic
4733523	NM_020442.6(VARS2):c.1650G>A (p.Trp550Ter)	Pathogenic
4777421	NM_020442.6(VARS2):c.1562G>A (p.Trp521Ter)	Pathogenic
4848726	NM_020442.6(VARS2):c.1443del (p.Phe481fs)	Pathogenic
520392	NM_006295.3(VARS1):c.2074G>C (p.Ala692Pro)	Pathogenic
520393	NM_006295.3(VARS1):c.1324C>T (p.Arg442Ter)	Pathogenic
561994	NM_006295.3(VARS1):c.1300C>G (p.Leu434Val)	Pathogenic
561995	NM_006295.3(VARS1):c.2464G>A (p.Gly822Ser)	Pathogenic
561998	NM_006295.3(VARS1):c.219_232dup (p.Leu78fs)	Pathogenic
590284	NM_006295.3(VARS1):c.1577-2A>G	Pathogenic
590285	NM_006295.3(VARS1):c.3192G>A (p.Met1064Ile)	Pathogenic
933236	NM_020442.6(VARS2):c.1060G>A (p.Asp354Asn)	Pathogenic
976680	NM_006295.3(VARS1):c.181G>T (p.Glu61Ter)	Pathogenic
997679	NM_020442.6(VARS2):c.2758T>C (p.Tyr920His)	Pathogenic
1029203	NM_020442.6(VARS2):c.2869_2876dup (p.Leu961fs)	Likely pathogenic

SpliceAI

8198 predictions. Top by Δscore:

Variant	Effect	Δscore
6:30915011:G:GT	donor_gain	1.0000
6:30915014:GC:G	donor_gain	1.0000
6:30915028:G:T	donor_gain	1.0000
6:30915154:A:AG	acceptor_gain	1.0000
6:30915155:G:GA	acceptor_gain	1.0000
6:30915851:G:GT	donor_gain	1.0000
6:30915876:G:T	donor_gain	1.0000
6:30915975:TTGCA:T	acceptor_loss	1.0000
6:30915976:TGCAG:T	acceptor_loss	1.0000
6:30915977:GCA:G	acceptor_loss	1.0000
6:30915978:CAGG:C	acceptor_loss	1.0000
6:30915979:A:AG	acceptor_gain	1.0000
6:30915979:A:G	acceptor_loss	1.0000
6:30915980:G:GG	acceptor_gain	1.0000
6:30915980:G:T	acceptor_loss	1.0000
6:30916034:G:GT	donor_gain	1.0000
6:30916048:G:GG	donor_gain	1.0000
6:30918916:G:GG	donor_gain	1.0000
6:30919756:A:AG	acceptor_gain	1.0000
6:30919757:G:GG	acceptor_gain	1.0000
6:30919847:GG:G	donor_gain	1.0000
6:30919848:GG:G	donor_gain	1.0000
6:30920330:CAGGG:C	acceptor_loss	1.0000
6:30920331:A:AG	acceptor_gain	1.0000
6:30920331:AG:A	acceptor_gain	1.0000
6:30920332:G:GG	acceptor_gain	1.0000
6:30920332:GG:G	acceptor_gain	1.0000
6:30920332:GGGT:G	acceptor_gain	1.0000
6:30920332:GGGTC:G	acceptor_gain	1.0000
6:30920434:CAG:C	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000311185 (6:31795737 G>T), RS1000403325 (6:31793828 C>T), RS1000411178 (6:31788147 G>A), RS1000415832 (6:31786325 C>A), RS1000463726 (6:31788455 A>G), RS1000642264 (6:31793960 C>T), RS1000921309 (6:31787288 T>C), RS1000966462 (6:31791893 C>G,T), RS1001402319 (6:31780345 T>G), RS1001580192 (6:31787774 C>T), RS1001950036 (6:31780312 A>G), RS1002060012 (6:31787841 G>A), RS1002139015 (6:31793031 C>T), RS1002482381 (6:31795567 G>A), RS1002612080 (6:31783381 G>A)

Disease associations

OMIM: gene MIM:192150 | disease phenotypes: MIM:617802, MIM:615917, MIM:609060

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy	Definitive	Autosomal recessive
combined oxidative phosphorylation defect type 20	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy	Definitive	AR
mitochondrial disease	Definitive	AR

Mondo (6): neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (MONDO:0060621), combined oxidative phosphorylation defect type 20 (MONDO:0014397), mitochondrial disease (MONDO:0044970), intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149), hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (MONDO:0012191)

Orphanet (4): Combined oxidative phosphorylation defect type 20 (Orphanet:420728), Mitochondrial disease (Orphanet:68380), Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (Orphanet:137681), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

60 total (30 of 60 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000237	Small anterior fontanelle
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000508	Ptosis
HP:0000527	Long eyelashes
HP:0000545	Myopia
HP:0000590	Progressive external ophthalmoplegia
HP:0000695	Natal tooth
HP:0000733	Motor stereotypy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001290	Generalized hypotonia
HP:0001321	Cerebellar hypoplasia
HP:0001324	Muscle weakness
HP:0001344	Absent speech
HP:0001518	Small for gestational age
HP:0001612	Weak cry
HP:0001622	Premature birth
HP:0001623	Breech presentation
HP:0001639	Hypertrophic cardiomyopathy

GWAS associations

61 associations (top):

Study	Trait	p-value
GCST000549_35	HIV-1 control	1.000000e-06
GCST000853_3	Ulcerative colitis	4.000000e-06
GCST001876_9	Pubertal anthropometrics	4.000000e-06
GCST004131_25	Inflammatory bowel disease	2.000000e-31
GCST004133_79	Ulcerative colitis	5.000000e-65
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_118	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_126	Autism spectrum disorder or schizophrenia	2.000000e-10
GCST004521_131	Autism spectrum disorder or schizophrenia	2.000000e-10
GCST004521_132	Autism spectrum disorder or schizophrenia	2.000000e-09
GCST004521_154	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_17	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_171	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_173	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_19	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_2	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_210	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_213	Autism spectrum disorder or schizophrenia	5.000000e-13
GCST004521_224	Autism spectrum disorder or schizophrenia	5.000000e-10
GCST004521_227	Autism spectrum disorder or schizophrenia	4.000000e-12
GCST004521_265	Autism spectrum disorder or schizophrenia	7.000000e-14
GCST004521_27	Autism spectrum disorder or schizophrenia	1.000000e-09
GCST004521_281	Autism spectrum disorder or schizophrenia	5.000000e-09
GCST004521_295	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_296	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_3	Autism spectrum disorder or schizophrenia	2.000000e-15
GCST004521_33	Autism spectrum disorder or schizophrenia	1.000000e-08

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0001382	puberty
EFO:0005091	monocyte count
EFO:0008378	mosquito bite reaction size measurement
EFO:0005112	gestational age
EFO:0005939	parental genotype effect measurement
EFO:0006336	diastolic blood pressure
EFO:0004531	urate measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007789	BMI-adjusted waist circumference

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
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C563797	Combined Oxidative Phosphorylation Deficiency 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2612 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.71	Kd	19.46	nM	CHEMBL5653589
7.71	ED50	19.46	nM	CHEMBL5653589
5.62	Kd	2385	nM	CHEMBL3752910
5.62	ED50	2385	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 10 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149755: Binding affinity to human VARS incubated for 45 mins by Kinobead based pull down assay	kd	0.0195	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149755: Binding affinity to human VARS incubated for 45 mins by Kinobead based pull down assay	kd	2.3855	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
Acetaminophen	decreases expression	3
ochratoxin A	decreases expression, increases expression	2
Cisplatin	decreases expression, increases expression	2
Smoke	decreases expression	2
Valproic Acid	affects expression, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
aflatoxin B2	decreases methylation	1
methacrylaldehyde	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
calfactant	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Zoledronic Acid	increases expression	1
Acrolein	affects cotreatment, increases expression	1
Arsenic	affects methylation	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652797	Binding	Binding affinity to human VARS 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)

300 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
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
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
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
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
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
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
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities