Combined oxidative phosphorylation defect type 27

Summary

Combined oxidative phosphorylation defect type 27 (MONDO:0014728) is a disease caused by CARS2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CARS2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 718
• Phenotypes (HPO): 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000529	Progressive visual loss	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0002133	Status epilepticus	Frequent (30-79%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0002273	Tetraparesis	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002500	Abnormal cerebral white matter morphology	Frequent (30-79%)
HP:0002506	Diffuse cerebral atrophy	Frequent (30-79%)
HP:0003200	Ragged-red muscle fibers	Frequent (30-79%)
HP:0008347	Decreased activity of mitochondrial complex IV	Frequent (30-79%)
HP:0011923	Decreased activity of mitochondrial complex I	Frequent (30-79%)
HP:0011924	Decreased activity of mitochondrial complex III	Frequent (30-79%)
HP:0031165	Multifocal seizures	Frequent (30-79%)
HP:0200134	Epileptic encephalopathy	Frequent (30-79%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0001790	Nonimmune hydrops fetalis	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0004305	Involuntary movements	Occasional (5-29%)
HP:0007351	Upper limb postural tremor	Occasional (5-29%)
HP:0010853	EEG with periodic lateralized epileptiform discharges	Occasional (5-29%)
HP:0012531	Pain	Occasional (5-29%)
HP:0025517	Hypoplastic hippocampus	Occasional (5-29%)
HP:0040288	Nasogastric tube feeding	Occasional (5-29%)
HP:0100275	Diffuse cerebellar atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	combined oxidative phosphorylation defect type 27
Mondo ID	MONDO:0014728
OMIM	616672
Orphanet	477774
DOID	DOID:0111489
UMLS	C5567608
MedGen	1799031
GARD	0017856
Is cancer (heuristic)	no

Also known as: CARS2 combined oxidative phosphorylation deficiency · combined oxidative phosphorylation deficiency 27 · combined oxidative phosphorylation deficiency caused by mutation in CARS2 · combined oxidative phosphorylation deficiency type 27 · COXPD27

Data availability: 718 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › combined oxidative phosphorylation deficiency › combined oxidative phosphorylation defect type 27

Related subtypes (57): severe X-linked mitochondrial encephalomyopathy, hepatoencephalopathy due to combined oxidative phosphorylation defect type 1, combined oxidative phosphorylation defect type 2, fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3, combined oxidative phosphorylation defect type 4, hypotonia with lactic acidemia and hyperammonemia, combined oxidative phosphorylation defect type 7, combined oxidative phosphorylation defect type 8, combined oxidative phosphorylation defect type 9, mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, combined oxidative phosphorylation defect type 11, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, combined oxidative phosphorylation defect type 13, combined oxidative phosphorylation defect type 14, combined oxidative phosphorylation defect type 15, infantile hypertrophic cardiomyopathy due to MRPL44 deficiency, combined oxidative phosphorylation defect type 17, growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome, combined oxidative phosphorylation deficiency 19, combined oxidative phosphorylation defect type 20, combined oxidative phosphorylation defect type 21, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation defect type 23, combined oxidative phosphorylation defect type 24, combined oxidative phosphorylation defect type 25, combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation deficiency 28, combined oxidative phosphorylation deficiency 29, combined oxidative phosphorylation defect type 30, lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome, combined oxidative phosphorylation deficiency 40, combined oxidative phosphorylation deficiency 41, combined oxidative phosphorylation deficiency 42, combined oxidative phosphorylation deficiency 43, combined oxidative phosphorylation deficiency 44, combined oxidative phosphorylation deficiency 52, combined oxidative phosphorylation deficiency 53, combined oxidative phosphorylation deficiency 54, combined oxidative phosphorylation deficiency 37, combined oxidative phosphorylation deficiency 38, combined oxidative phosphorylation deficiency 39, combined oxidative phosphorylation deficiency 45, combined oxidative phosphorylation deficiency 46, combined oxidative phosphorylation deficiency 47, combined oxidative phosphorylation deficiency 48, combined oxidative phosphorylation deficiency 51, combined oxidative phosphorylation deficiency 32, combined oxidative phosphorylation deficiency 33, combined oxidative phosphorylation deficiency 34, combined oxidative phosphorylation deficiency 35, combined oxidative phosphorylation deficiency 36, combined oxidative phosphorylation deficiency 55, combined oxidative phosphorylation deficiency 56, combined oxidative phosphorylation deficiency 57, combined oxidative phosphorylation deficiency 58, combined oxidative phosphorylation deficiency 59, combined oxidative phosphorylation deficiency 60

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

298 likely benign, 255 uncertain significance, 15 conflicting classifications of pathogenicity, 15 benign, 13 benign/likely benign, 3 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
521824	NM_024537.4(CARS2):c.1360dup (p.Ile454fs)	CARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
180135	NM_024537.4(CARS2):c.655G>A (p.Ala219Thr)	CARS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3377435	NM_024537.4(CARS2):c.1238_1239insC (p.Phe414_Asp415insTer)	CARS2	Likely pathogenic	criteria provided, single submitter
4849456	NM_024537.4(CARS2):c.466-2A>G	CARS2	Likely pathogenic	criteria provided, single submitter
1081523	NM_024537.4(CARS2):c.1566G>A (p.Leu522=)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1193396	NM_024537.4(CARS2):c.1084C>T (p.Gln362Ter)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1212666	NM_024537.4(CARS2):c.125G>C (p.Trp42Ser)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1473024	NM_024537.4(CARS2):c.781G>T (p.Ala261Ser)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2083473	NM_024537.4(CARS2):c.1068dup (p.Asp357Ter)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218177	NM_024537.4(CARS2):c.649_651del (p.Glu217del)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265071	NM_024537.4(CARS2):c.2T>C (p.Met1Thr)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
450267	NM_024537.4(CARS2):c.878_879del (p.Phe293fs)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475624	NM_024537.4(CARS2):c.1632C>A (p.Ser544Arg)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475625	NM_024537.4(CARS2):c.1683dup (p.Ser562fs)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475628	NM_024537.4(CARS2):c.302G>A (p.Arg101Gln)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475632	NM_024537.4(CARS2):c.574A>G (p.Asn192Asp)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
542307	NM_024537.4(CARS2):c.244G>A (p.Val82Ile)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
542311	NM_024537.4(CARS2):c.1535G>A (p.Arg512Gln)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
650817	NM_024537.4(CARS2):c.1075G>A (p.Ala359Thr)	CARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001034	NM_024537.4(CARS2):c.84G>T (p.Trp28Cys)	CARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1002431	NM_024537.4(CARS2):c.1013A>G (p.Asp338Gly)	CARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1004370	NM_024537.4(CARS2):c.1168G>C (p.Val390Leu)	CARS2	Uncertain significance	criteria provided, single submitter
1004823	NM_024537.4(CARS2):c.1321C>A (p.Pro441Thr)	CARS2	Uncertain significance	criteria provided, single submitter
1004974	NM_024537.4(CARS2):c.527T>G (p.Ile176Ser)	CARS2	Uncertain significance	criteria provided, single submitter
1009783	NM_024537.4(CARS2):c.1025TCT[1] (p.Phe343del)	CARS2	Uncertain significance	criteria provided, single submitter
1009930	NM_024537.4(CARS2):c.149C>T (p.Thr50Met)	CARS2	Uncertain significance	criteria provided, single submitter
1010149	NM_024537.4(CARS2):c.1623+1G>C	CARS2	Uncertain significance	criteria provided, single submitter
1010501	NM_024537.4(CARS2):c.1138T>C (p.Tyr380His)	CARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1010611	NM_024537.4(CARS2):c.1570G>C (p.Glu524Gln)	CARS2	Uncertain significance	criteria provided, single submitter
1010736	NM_024537.4(CARS2):c.73G>A (p.Gly25Arg)	CARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CARS2	Strong	Autosomal recessive	combined oxidative phosphorylation defect type 27	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CARS2	Orphanet:477774	Combined oxidative phosphorylation defect type 27

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CARS2	HGNC:25695	ENSG00000134905	Q9HA77	Probable cysteine–tRNA ligase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CARS2	Probable cysteine–tRNA ligase, mitochondrial	Mitochondrial cysteine-specific aminoacyl-tRNA synthetase that catalyzes the ATP-dependent ligation of cysteine to tRNA(Cys).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CARS2	Enzyme (other)	yes	6.1.1.16	tRNAsynth_Ia_anticodon-bd, Rossmann-like_a/b/a_fold, Cys-tRNA-ligase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CARS2	273	ubiquitous	marker	monocyte, mononuclear cell, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CARS2	2,256

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CARS2	Q9HA77	86.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial tRNA aminoacylation	1	519.1×	0.007	CARS2
tRNA Aminoacylation	1	285.5×	0.007	CARS2
Translation	1	62.1×	0.021	CARS2
Metabolism of proteins	1	12.4×	0.081	CARS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cysteinyl-tRNA aminoacylation	1	8426.0×	1e-04	CARS2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CARS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CARS2	6.1.1.16	cysteine-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CARS2
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CARS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.