CARS2

Summary

CARS2 (cysteinyl-tRNA synthetase 2, mitochondrial, HGNC:25695) is a protein-coding gene on chromosome 13q34, encoding Probable cysteine–tRNA ligase, mitochondrial (Q9HA77). Mitochondrial cysteine-specific aminoacyl-tRNA synthetase that catalyzes the ATP-dependent ligation of cysteine to tRNA(Cys). It is a selective cancer dependency (DepMap: 24.7% of cell lines).

This gene encodes a putative member of the class I family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. This protein is encoded by the nuclear genome but is likely to be imported to the mitochondrion where it is thought to catalyze the ligation of cysteine to tRNA molecules. A splice-site mutation in this gene has been associated with a novel progressive myoclonic epilepsy disease with similar symptoms to MERRF syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 79587 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined oxidative phosphorylation defect type 27 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 861 total — 2 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 55
• Cancer dependency (DepMap): dependent in 24.7% of screened cell lines
• MANE Select transcript: NM_024537

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25695
Approved symbol	CARS2
Name	cysteinyl-tRNA synthetase 2, mitochondrial
Location	13q34
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12118
Ensembl gene	ENSG00000134905
Ensembl biotype	protein_coding
OMIM	612800
Entrez	79587

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 14 retained_intron, 12 protein_coding, 12 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000257347, ENST00000375781, ENST00000465145, ENST00000471986, ENST00000480437, ENST00000481787, ENST00000485188, ENST00000487253, ENST00000535398, ENST00000535516, ENST00000535615, ENST00000537386, ENST00000537394, ENST00000537404, ENST00000537412, ENST00000537743, ENST00000537802, ENST00000539269, ENST00000539405, ENST00000540006, ENST00000540215, ENST00000540629, ENST00000540785, ENST00000541239, ENST00000541362, ENST00000541443, ENST00000542126, ENST00000542709, ENST00000542774, ENST00000543487, ENST00000544488, ENST00000545506, ENST00000620794, ENST00000890913, ENST00000890914, ENST00000890915, ENST00000939450, ENST00000939451, ENST00000939452, ENST00000939453, ENST00000960810

RefSeq mRNA: 2 — MANE Select: NM_024537 NM_001352252, NM_024537

CCDS: CCDS9514

Canonical transcript exons

ENST00000257347 — 15 exons

Exon	Start	End
ENSE00002270126	110705870	110706116
ENSE00003463053	110701438	110701555
ENSE00003466043	110667340	110667473
ENSE00003468125	110687947	110688018
ENSE00003505978	110642315	110642521
ENSE00003534434	110647101	110647239
ENSE00003538335	110645967	110646090
ENSE00003538808	110641417	110641608
ENSE00003547879	110663451	110663518
ENSE00003557809	110676974	110677103
ENSE00003574038	110644385	110644483
ENSE00003575575	110651034	110651100
ENSE00003606806	110687721	110687826
ENSE00003630665	110705521	110705571
ENSE00003657475	110683051	110683134

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 97.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.7550 / max 609.8672, expressed in 1826 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138260	47.2357	1826
138261	0.6998	443
138262	0.6699	407
138259	0.5942	393
138257	0.5667	87
138264	0.4579	253
138256	0.4255	84
138265	0.0720	19
138258	0.0334	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	97.56	gold quality
mononuclear cell	CL:0000842	97.50	gold quality
granulocyte	CL:0000094	97.44	gold quality
leukocyte	CL:0000738	97.33	gold quality
adenohypophysis	UBERON:0002196	95.61	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.51	gold quality
stromal cell of endometrium	CL:0002255	95.27	gold quality
blood	UBERON:0000178	95.21	gold quality
cerebellar hemisphere	UBERON:0002245	95.21	gold quality
mucosa of transverse colon	UBERON:0004991	95.21	gold quality
decidua	UBERON:0002450	95.18	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.15	gold quality
apex of heart	UBERON:0002098	95.13	gold quality
cerebellar cortex	UBERON:0002129	95.09	gold quality
left uterine tube	UBERON:0001303	95.02	gold quality
right adrenal gland	UBERON:0001233	94.90	gold quality
right adrenal gland cortex	UBERON:0035827	94.90	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.89	gold quality
spleen	UBERON:0002106	94.81	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.79	gold quality
pituitary gland	UBERON:0000007	94.77	gold quality
right testis	UBERON:0004534	94.67	gold quality
lower esophagus mucosa	UBERON:0035834	94.66	gold quality
right ovary	UBERON:0002118	94.62	gold quality
body of uterus	UBERON:0009853	94.57	gold quality
endocervix	UBERON:0000458	94.54	gold quality
skin of abdomen	UBERON:0001416	94.52	gold quality
skin of leg	UBERON:0001511	94.50	gold quality
left adrenal gland cortex	UBERON:0035825	94.45	gold quality
left ovary	UBERON:0002119	94.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.54

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4

miRNA regulators (miRDB)

9 targeting CARS2, 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-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-4725-5P	98.67	65.42	628
HSA-MIR-504-5P	98.67	65.40	631
HSA-MIR-656-5P	96.82	67.67	372
HSA-MIR-3655	86.11	61.77	117

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 24.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 2)

• CARS2 is a novel disease gene associated with a severe progressive myoclonic epilepsy most resembling MERRF syndrome (PMID:25361775)
• Mutations in CARS2 result in a mitochondrial translational defect as seen in individuals with mitochondrial epileptic encephalopathy. (PMID:25787132)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cars2	ENSDARG00000078546
mus_musculus	Cars2	ENSMUSG00000056228
rattus_norvegicus	Cars2	ENSRNOG00000014526
drosophila_melanogaster	CysRS-m	FBGN0033900

Paralogs (1): CARS1 (ENSG00000110619)

Protein

Protein identifiers

Probable cysteine–tRNA ligase, mitochondrial — Q9HA77 (reviewed: Q9HA77)

Alternative names: Cysteinyl-tRNA synthetase

All UniProt accessions (7): A0A087WWV1, Q9HA77, F5H579, F5H623, H0YFF0, H0YFV1, H0YGF2

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial cysteine-specific aminoacyl-tRNA synthetase that catalyzes the ATP-dependent ligation of cysteine to tRNA(Cys). In addition to its role as an aminoacyl-tRNA synthetase, has also cysteine persulfide synthase activity. Produces reactive persulfide species such as cysteine persulfide (CysSSH) from substrate cysteine and mediate direct incorporation of CysSSH into proteins during translations, resulting in protein persulfides and polysulfides. CysSSHs behave as potent antioxidants and cellular protectants.

Subcellular location. Mitochondrion.

Disease relevance. Combined oxidative phosphorylation deficiency 27 (COXPD27) [MIM:616672] An autosomal recessive mitochondrial disorder characterized by multiple mitochondrial respiratory-chain-complex deficiencies causing neurological regression, progressive cognitive decline, complex movement disorder, epileptic encephalopathy, progressive spastic tetraparesis, and progressive impairment of vision and hearing. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. ‘KIIK’ region and ‘KMSKS’ region are required for cysteine persulfide synthase activity.

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

RefSeq proteins (2): NP_001339181, NP_078813* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009080	tRNAsynth_Ia_anticodon-bd	Homologous_superfamily
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR015803	Cys-tRNA-ligase	Family
IPR024909	Cys-tRNA/MSH_ligase	Family
IPR032678	tRNA-synt_1_cat_dom	Domain

Pfam: PF01406

Enzyme classification (BRENDA):

• EC 6.1.1.16 — cysteine-tRNA ligase (BRENDA: 24 organisms, 36 substrates, 66 inhibitors, 100 Km, 72 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
TRNACYS	0.0003–0.095	26
L-CYSTEINE	0.0005–3.61	23
ATP	0.057–1.8	22
CYS	0.03–0.17	5
SELENOCYSTEINE	0.0016–0.063	5
DIPHOSPHATE	0.16–1	3
2-AMINOBUTYRIC ACID	10	1
L-CYS	0.0125	1
TRNA1CYS	0.08	1
TRNA1CYSA33U	0.09	1
TRNA2CYS	0.16	1
TRNA3CYS	0.14	1
TRNA3CYSC20U/U21C/A44U/C46A/A47G	0.11	1
TRNA3CYSC20U/U21C/A44U/C46A/A47G/G57A	0.09	1
TRNA3CYSG57A	0.12	1

Catalyzed reactions (Rhea), 5 shown:

• tRNA(Cys) + L-cysteine + ATP = L-cysteinyl-tRNA(Cys) + AMP + diphosphate (RHEA:17773)
• 2 L-cysteine = S-sulfanyl-L-cysteine + L-alanine (RHEA:78543)
• S-sulfanyl-L-cysteine + L-cysteine = S-disulfanyl-L-cysteine + L-alanine (RHEA:78627)
• S-sulfanyl-L-cysteine + tRNA(Cys) + ATP = (S)-sulfanyl-L-cysteinyl-tRNA(Cys) + AMP + diphosphate (RHEA:78647)
• S-disulfanyl-L-cysteine + tRNA(Cys) + ATP = (S)-disulfanyl-L-cysteinyl-tRNA(Cys) + AMP + diphosphate (RHEA:78651)

UniProt features (25 total): binding site 8, sequence variant 5, mutagenesis site 4, short sequence motif 3, sequence conflict 3, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HA77-F1	86.68	0.68

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 (8): 282; 286; 320; 78; 79; 119; 257; 282

Mutagenesis-validated functional residues (4):

Position	Phenotype
78	no effect on cysteine persulfide synthase activity; when associated with d-257. loss of cysteine–trna ligase activity;
124–127	no effect on cysteine–trna ligase activity. loss of cysteine persulfide synthase activity.
257	no effect on cysteine persulfide synthase activity; when associated with d-78. loss of cysteine–trna ligase activity; w
317–320	no effect on cysteine–trna ligase activity. loss of cysteine persulfide synthase 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: 213 (showing top): GOBP_AMINO_ACID_ACTIVATION, GOBP_TRNA_METABOLIC_PROCESS, GOBP_TRANSLATION, chr13q34, KEGG_AMINOACYL_TRNA_BIOSYNTHESIS, REACTOME_MITOCHONDRIAL_TRNA_AMINOACYLATION, DOUGLAS_BMI1_TARGETS_UP, VANHARANTA_UTERINE_FIBROID_WITH_7Q_DELETION_UP, GOMF_LIGASE_ACTIVITY_FORMING_CARBON_OXYGEN_BONDS, GOMF_ADENYL_NUCLEOTIDE_BINDING, KRIEG_HYPOXIA_NOT_VIA_KDM3A, GOMF_CATALYTIC_ACTIVITY_ACTING_ON_RNA, GOMF_CATALYTIC_ACTIVITY_ACTING_ON_A_TRNA, STK33_DN, STK33_NOMO_DN

GO Biological Process (3): cysteinyl-tRNA aminoacylation (GO:0006423), translation (GO:0006412), tRNA aminoacylation for protein translation (GO:0006418)

GO Molecular Function (6): cysteine-tRNA ligase activity (GO:0004817), ATP binding (GO:0005524), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), ligase activity (GO:0016874)

GO Cellular Component (2): cytoplasm (GO:0005737), mitochondrion (GO:0005739)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
tRNA Aminoacylation	1
Translation	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
tRNA 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
translation	1
tRNA aminoacylation	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate 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
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2092 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CARS2	IARS2	Q9NSE4	902
CARS2	PARS2	Q7L3T8	888
CARS2	LARS2	Q15031	884
CARS2	IARS1	P41252	883
CARS2	LARS1	Q9P2J5	875
CARS2	SARS1	P49591	864
CARS2	M0R2C6	M0R2C6	856
CARS2	SARS2	Q9NP81	856
CARS2	NARS2	Q96I59	844
CARS2	VARS1	P26640	842
CARS2	RARS2	Q5T160	839
CARS2	VARS2	Q5ST30	829
CARS2	AARS1	P49588	811
CARS2	QARS1	P47897	810
CARS2	MARS1	P56192	810
CARS2	EARS2	Q5JPH6	810
CARS2	YARS2	Q9Y2Z4	810

IntAct

32 interactions, top by confidence:

A	B	Type	Score
TRMT61B	GLS	psi-mi:“MI:0914”(association)	0.480
GABARAP	CARS2	psi-mi:“MI:0407”(direct interaction)	0.440
GABARAPL1	CARS2	psi-mi:“MI:0407”(direct interaction)	0.440
GABARAPL2	CARS2	psi-mi:“MI:0407”(direct interaction)	0.440
MAP1LC3A	CARS2	psi-mi:“MI:0407”(direct interaction)	0.440
PNMA8A	CARS2	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
SPG11	CARS2	psi-mi:“MI:0915”(physical association)	0.370
CAPN1	ANKRD17	psi-mi:“MI:0914”(association)	0.350
OXLD1	NUDT19	psi-mi:“MI:0914”(association)	0.350
TRMT61B		psi-mi:“MI:0914”(association)	0.350
RGCC	TRAF7	psi-mi:“MI:0914”(association)	0.350
MRPL18		psi-mi:“MI:0914”(association)	0.350
OXLD1	PRORP	psi-mi:“MI:0914”(association)	0.350
LYPD2	PLXNA2	psi-mi:“MI:0914”(association)	0.350
TCEAL9	DIRAS1	psi-mi:“MI:0914”(association)	0.350
COCH	HSPA5	psi-mi:“MI:0914”(association)	0.350
RGCC	VASP	psi-mi:“MI:0914”(association)	0.350
SLC25A22	EIF3CL	psi-mi:“MI:0914”(association)	0.350
FECH	GTPBP10	psi-mi:“MI:0914”(association)	0.350
CLPP	NDUFA4	psi-mi:“MI:2364”(proximity)	0.270
AURKAIP1	VWA8	psi-mi:“MI:2364”(proximity)	0.270
	VWA8	psi-mi:“MI:2364”(proximity)	0.270
HSPD1	VWA8	psi-mi:“MI:2364”(proximity)	0.270
MGST3	VWA8	psi-mi:“MI:2364”(proximity)	0.270
PDK1	VWA8	psi-mi:“MI:2364”(proximity)	0.270
TRMT61B	VWA8	psi-mi:“MI:2364”(proximity)	0.270
IMMP2L	MRPL45	psi-mi:“MI:2364”(proximity)	0.270
KCNK3	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (132): CARS2 (Affinity Capture-MS), CARS2 (Affinity Capture-MS), CARS2 (Affinity Capture-MS), CARS2 (Synthetic Growth Defect), CARS2 (Synthetic Growth Defect), CARS2 (Affinity Capture-MS), CARS2 (Affinity Capture-MS), CARS2 (Affinity Capture-MS), CARS2 (Affinity Capture-MS), DONSON (Negative Genetic), FH (Positive Genetic), LEO1 (Positive Genetic), MED14 (Negative Genetic), PGK1 (Negative Genetic), PSMB6 (Negative Genetic)

ESM2 similar proteins: A0A1D6LAG9, A2YQ56, A6H7E1, B3LFA4, B8B4H5, B9FK36, B9FSH5, F4I1L3, F4IPY2, F4KE63, O23247, O24357, O75005, P49589, P49696, P93736, Q0IZQ2, Q2KIF8, Q2QMG2, Q43727, Q43768, Q43794, Q43839, Q499X9, Q4R646, Q5M7N8, Q5ZKA2, Q69UZ3, Q6DJ95, Q6GQJ7, Q6PA41, Q7T0Z0, Q8BIJ6, Q8BYM8, Q8L743, Q8L785, Q8RXE9, Q8RXK8, Q8S6N5, Q90YI3

Diamond homologs: A0LIR9, A0PXS5, A0R8G1, A1RYM3, A2BXK1, A3DLW5, A3N0S3, A4IJG8, A4J0Y9, A5D5M0, A5F763, A5IBG0, A6UP68, A6UWT0, A6VG07, A6VQ79, A7GK01, A8FTH6, A9AAN8, A9KBJ2, A9N924, A9VNA2, B0BPJ8, B0K5F6, B0KCH9, B0TC35, B2IEE1, B2V6B4, B3GXR0, B6YUQ3, B7GJ46, B7HJ28, B7HQS4, B7ISZ9, B7JK97, B7VGZ1, B8F392, B8GNT5, B9IZH4, C0QRE6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ATF4	“up-regulates quantity by expression”	CARS2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	4
Uncertain significance	386
Likely benign	342
Benign	71

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1457975	NC_000013.10:g.(?110802675)(111358440_?)del	Pathogenic
521824	NM_024537.4(CARS2):c.1360dup (p.Ile454fs)	Pathogenic
180135	NM_024537.4(CARS2):c.655G>A (p.Ala219Thr)	Likely pathogenic
3377435	NM_024537.4(CARS2):c.1238_1239insC (p.Phe414_Asp415insTer)	Likely pathogenic
4849456	NM_024537.4(CARS2):c.466-2A>G	Likely pathogenic
972919	NM_024537.4(CARS2):c.1426G>T (p.Gly476Ter)	Likely pathogenic

SpliceAI

3474 predictions. Top by Δscore:

Variant	Effect	Δscore
13:110642310:CTCA:C	donor_loss	1.0000
13:110642311:TCA:T	donor_loss	1.0000
13:110642312:CA:C	donor_loss	1.0000
13:110642313:A:AC	donor_gain	1.0000
13:110642313:AC:A	donor_gain	1.0000
13:110642313:ACCT:A	donor_loss	1.0000
13:110642314:C:A	donor_loss	1.0000
13:110642314:C:CC	donor_gain	1.0000
13:110642314:CC:C	donor_gain	1.0000
13:110642517:ACGTA:A	acceptor_gain	1.0000
13:110642518:CGTA:C	acceptor_gain	1.0000
13:110642518:CGTAC:C	acceptor_gain	1.0000
13:110644063:A:AC	donor_gain	1.0000
13:110644064:C:CC	donor_gain	1.0000
13:110644064:CTGTG:C	donor_gain	1.0000
13:110644380:CCTA:C	donor_loss	1.0000
13:110644381:CTAC:C	donor_loss	1.0000
13:110644382:TAC:T	donor_loss	1.0000
13:110644383:ACC:A	donor_loss	1.0000
13:110645978:C:CA	donor_gain	1.0000
13:110646026:C:CT	donor_gain	1.0000
13:110646087:GAGC:G	acceptor_gain	1.0000
13:110646089:GC:G	acceptor_gain	1.0000
13:110646090:CC:C	acceptor_gain	1.0000
13:110646091:C:CC	acceptor_gain	1.0000
13:110646091:C:CG	acceptor_loss	1.0000
13:110646092:T:C	acceptor_loss	1.0000
13:110647095:TCTTA:T	donor_loss	1.0000
13:110647096:CTTA:C	donor_loss	1.0000
13:110647097:TTA:T	donor_loss	1.0000

AlphaMissense

3681 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:110677002:A:G	W253R	0.997
13:110677002:A:T	W253R	0.997
13:110677065:A:G	W232R	0.997
13:110677065:A:T	W232R	0.997
13:110705537:G:C	H87D	0.997
13:110663478:T:A	K320N	0.996
13:110663478:T:G	K320N	0.996
13:110667415:G:C	H282D	0.996
13:110677000:C:A	W253C	0.995
13:110677000:C:G	W253C	0.995
13:110705535:G:C	H87Q	0.995
13:110705535:G:T	H87Q	0.995
13:110705524:G:T	A91D	0.994
13:110705528:G:C	H90D	0.994
13:110667401:T:A	E286D	0.993
13:110667401:T:G	E286D	0.993
13:110667429:T:C	D277G	0.993
13:110677072:G:C	F229L	0.993
13:110677072:G:T	F229L	0.993
13:110677074:A:G	F229L	0.993
13:110701538:T:A	D98V	0.993
13:110705560:C:T	G79E	0.993
13:110663479:T:A	K320I	0.992
13:110663480:T:C	K320E	0.992
13:110667419:A:C	F280L	0.992
13:110667419:A:T	F280L	0.992
13:110667421:A:G	F280L	0.992
13:110701547:A:T	V95D	0.992
13:110705526:A:C	H90Q	0.992
13:110705526:A:T	H90Q	0.992

dbSNP variants (sampled 300 via entrez): RS1000008957 (13:110696577 T>C,G), RS1000061257 (13:110703494 C>T), RS1000105735 (13:110661895 A>G), RS1000170352 (13:110645080 G>A,T), RS1000187560 (13:110685776 G>T), RS1000194506 (13:110675781 C>T), RS1000212404 (13:110688242 T>C), RS1000242115 (13:110686048 G>C), RS1000242791 (13:110679857 G>C), RS1000367388 (13:110667433 T>A), RS1000384965 (13:110691595 A>C,G), RS1000416268 (13:110691871 C>T), RS1000457068 (13:110672804 T>C), RS1000478005 (13:110661454 G>A), RS1000478664 (13:110713607 G>A)

Disease associations

OMIM: gene MIM:612800 | disease phenotypes: MIM:616672, MIM:125851

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation defect type 27	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Moderate	AR

Mondo (3): combined oxidative phosphorylation defect type 27 (MONDO:0014728), maturity-onset diabetes of the young type 2 (MONDO:0007453), microcephaly (MONDO:0001149)

Orphanet (2): Combined oxidative phosphorylation defect type 27 (Orphanet:477774), MODY (Orphanet:552)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000505	Visual impairment
HP:0000529	Progressive visual loss
HP:0000729	Autistic behavior
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001321	Cerebellar hypoplasia
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001344	Absent speech
HP:0001414	Microvesicular hepatic steatosis
HP:0001508	Failure to thrive
HP:0001790	Nonimmune hydrops fetalis
HP:0001987	Hyperammonemia
HP:0002015	Dysphagia
HP:0002059	Cerebral atrophy
HP:0002069	Bilateral tonic-clonic seizure
HP:0002072	Chorea
HP:0002079	Hypoplasia of the corpus callosum
HP:0002120	Cerebral cortical atrophy
HP:0002123	Generalized myoclonic seizure
HP:0002133	Status epilepticus
HP:0002151	Increased circulating lactate concentration
HP:0002179	Opisthotonus

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003671_11	Diastolic blood pressure	2.000000e-06
GCST012431_13	Parkinson’s disease	1.000000e-07
GCST012431_7	Parkinson’s disease	2.000000e-10
GCST90011899_7	Aspartate aminotransferase levels	3.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression	3
sodium arsenite	increases abundance, increases expression, affects methylation, decreases expression	3
Acetaminophen	affects cotreatment, decreases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
bisphenol F	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzo(a)pyrene	affects methylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Diethylstilbestrol	decreases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	increases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Methapyrilene	decreases methylation	1
Methyl Methanesulfonate	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B5RW	BCHCNi001-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02971202	PHASE1	COMPLETED	Contribution of Hyperinsulinemia vs. Hyperglycemia to Insulin Resistance in Type 1 Diabetes and Maturity Onset Diabetes of the Young, Type 2 (MODY2)
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.