Combined oxidative phosphorylation defect type 24

Summary

Combined oxidative phosphorylation defect type 24 (MONDO:0014547) is a disease caused by NARS2 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NARS2 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 53

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

Identifiers

Disease identifiers

Field	Value
Canonical name	combined oxidative phosphorylation defect type 24
Mondo ID	MONDO:0014547
OMIM	616239
Orphanet	444458
DOID	DOID:0111485
UMLS	C4015643
MedGen	864080
GARD	0017765
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation deficiency 24 · combined oxidative phosphorylation deficiency caused by mutation in NARS2 · combined oxidative phosphorylation deficiency type 24 · COXPD24 · NARS2 combined oxidative phosphorylation deficiency

Data availability: 53 ClinVar variants · 5 GenCC gene-disease records.

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 24

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 25, combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation defect type 27, 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

53 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 12 pathogenic, 10 likely pathogenic, 8 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 2 benign, 1 not provided, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323326	NM_024678.6(NARS2):c.1236C>G (p.Tyr412Ter)	NARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1683378	NM_024678.6(NARS2):c.947del (p.Asn316fs)	NARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183150	NM_024678.6(NARS2):c.822G>C (p.Gln274His)	NARS2	Pathogenic	no assertion criteria provided
2413140	NM_024678.6(NARS2):c.595-1G>A	NARS2	Pathogenic	criteria provided, single submitter
2431370	NC_000011.10:g.(78476711_78486359)del	NARS2	Pathogenic	criteria provided, single submitter
2682376	NC_000011.9:g.(78180360_78189483)_(78189730_78204108)del	NARS2	Pathogenic	criteria provided, single submitter
3254561	NM_024678.6(NARS2):c.936_949dup (p.Asn317delinsIleCysTer)	NARS2	Pathogenic	criteria provided, single submitter
3891808	NM_024678.6(NARS2):c.563_564del (p.Asp187_Ser188insTer)	NARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
391671	NM_024678.6(NARS2):c.418C>T (p.Arg140Ter)	NARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
4526064	NM_024678.6(NARS2):c.947dup (p.Asn316fs)	NARS2	Pathogenic	criteria provided, single submitter
632571	NM_024678.6(NARS2):c.969T>A (p.Tyr323Ter)	NARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632573	NM_024678.6(NARS2):c.594+1G>A	NARS2	Pathogenic	no assertion criteria provided
632577	NM_024678.6(NARS2):c.707T>G (p.Phe236Cys)	NARS2	Pathogenic	no assertion criteria provided
632578	NM_024678.6(NARS2):c.1184T>G (p.Leu395Arg)	NARS2	Pathogenic	no assertion criteria provided
872894	NM_024678.6(NARS2):c.545T>A (p.Ile182Lys)	NARS2	Pathogenic	criteria provided, single submitter
4278450	NM_005249.5(FOXG1):c.1002C>A (p.Tyr334Ter)	FOXG1	Likely pathogenic	criteria provided, single submitter
632572	NM_024678.6(NARS2):c.1142A>G (p.Asn381Ser)	LOC130006506	Likely pathogenic	criteria provided, single submitter
1341731	NM_024678.6(NARS2):c.822+6704_959+1727del	NARS2	Likely pathogenic	criteria provided, single submitter
183151	NM_024678.6(NARS2):c.641C>T (p.Pro214Leu)	NARS2	Likely pathogenic	criteria provided, single submitter
2413142	NM_024678.6(NARS2):c.959+1505T>G	NARS2	Likely pathogenic	criteria provided, single submitter
2413143	NM_024678.6(NARS2):c.822+6703_959+1726del	NARS2	Likely pathogenic	criteria provided, single submitter
3600372	NM_024678.6(NARS2):c.252-2A>G	NARS2	Likely pathogenic	criteria provided, single submitter
424270	NM_024678.6(NARS2):c.631T>A (p.Phe211Ile)	NARS2	Likely pathogenic	criteria provided, single submitter
1067185	NM_001283009.2(RTEL1):c.2265+1G>T	RTEL1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4278969	NM_001098484.3(SLC4A4):c.1015G>A (p.Glu339Lys)	SLC4A4	Likely pathogenic	criteria provided, single submitter
1691418	NM_024678.6(NARS2):c.1141A>G (p.Asn381Asp)	LOC130006506	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029917	NM_024678.6(NARS2):c.847A>G (p.Thr283Ala)	NARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1297024	NM_024678.6(NARS2):c.1291T>C (p.Tyr431His)	NARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3769681	NM_024678.6(NARS2):c.1025A>T (p.Glu342Val)	NARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
377031	NM_024678.6(NARS2):c.506T>A (p.Phe169Tyr)	NARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 10 · 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
NARS2	Definitive	Autosomal recessive	combined oxidative phosphorylation defect type 24	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NARS2	Orphanet:444458	Combined oxidative phosphorylation defect type 24
NARS2	Orphanet:79134	DEND syndrome
NARS2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
SLC4A4	Orphanet:93607	Autosomal recessive proximal renal tubular acidosis
RTEL1	Orphanet:1775	Dyskeratosis congenita
RTEL1	Orphanet:2032	Idiopathic pulmonary fibrosis
RTEL1	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
FOXG1	Orphanet:261144	FOXG1 syndrome due to 14q12 microdeletion
FOXG1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
FOXG1	Orphanet:598164	FOXG1 syndrome due to intragenic alteration

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NARS2	HGNC:26274	ENSG00000137513	Q96I59	Asparaginyl-tRNA synthetase	gencc,clinvar
SLC4A4	HGNC:11030	ENSG00000080493	Q9Y6R1	Electrogenic sodium bicarbonate cotransporter 1	clinvar
RTEL1	HGNC:15888	ENSG00000258366	Q9NZ71	Regulator of telomere elongation helicase 1	clinvar
FOXG1	HGNC:3811	ENSG00000176165	P55316	Forkhead box protein G1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NARS2	Asparaginyl-tRNA synthetase	Mitochondrial aminoacyl-tRNA synthetase that catalyzes the specific attachment of the asparagine amino acid (aa) to the homologous transfer RNA (tRNA), further participating in protein synthesis.
SLC4A4	Electrogenic sodium bicarbonate cotransporter 1	Electrogenic sodium/bicarbonate cotransporter with a Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3.
RTEL1	Regulator of telomere elongation helicase 1	A probable ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair and the maintenance of genomic stability.
FOXG1	Forkhead box protein G1	Transcription repression factor which plays an important role in the establishment of the regional subdivision of the developing brain and in the development of the telencephalon.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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	3.0×	0.605
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NARS2	Enzyme (other)	yes	6.1.1.22	Asp/Asn-tRNA-synth_IIb, Aa-tRNA-synt_II, NA-bd_OB_tRNA
SLC4A4	Other/Unknown	no		HCO3_transpt_euk, Na/HCO3_transpt, HCO3_transpt-like_TM_dom
RTEL1	Other/Unknown	no		Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
FOXG1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
secondary oocyte	1
skeletal muscle tissue of biceps brachii	1
jejunal mucosa	1
lateral globus pallidus	1
mucosa of sigmoid colon	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
sural nerve	1
Brodmann (1909) area 23	1
cortical plate	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NARS2	278	ubiquitous	marker	secondary oocyte, oocyte, skeletal muscle tissue of biceps brachii
SLC4A4	268	ubiquitous	marker	jejunal mucosa, lateral globus pallidus, mucosa of sigmoid colon
RTEL1	134	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
FOXG1	100	broad	marker	cortical plate, endothelial cell, Brodmann (1909) area 23

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RTEL1	2,324
NARS2	2,248
SLC4A4	1,799
FOXG1	106

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RTEL1	Q9NZ71	3
SLC4A4	Q9Y6R1	1
FOXG1	P55316	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NARS2	Q96I59	91.59

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC4A4 causes renal tubular acidosis, proximal, with ocular abnormalities and mental retardation (pRTA-OA)	1	1427.5×	0.020	SLC4A4
Bicarbonate transporters	1	285.5×	0.029	SLC4A4
Cytosolic iron-sulfur cluster assembly	1	190.3×	0.029	RTEL1
FOXO-mediated transcription of cell cycle genes	1	167.9×	0.029	FOXG1
Resolution of D-Loop Structures	1	158.6×	0.029	RTEL1
Extension of Telomeres	1	150.3×	0.029	RTEL1
Mitochondrial tRNA aminoacylation	1	129.8×	0.029	NARS2
Telomere Extension By Telomerase	1	114.2×	0.029	RTEL1
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	98.5×	0.029	RTEL1
Telomere Maintenance	1	92.1×	0.029	RTEL1
Regulation of MECP2 expression and activity	1	92.1×	0.029	FOXG1
Homology Directed Repair	1	77.2×	0.029	RTEL1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	77.2×	0.029	RTEL1
tRNA Aminoacylation	1	71.4×	0.029	NARS2
DNA Double-Strand Break Repair	1	62.1×	0.031	RTEL1
Developmental Lineage of Pancreatic Ductal Cells	1	57.1×	0.031	SLC4A4
Chromosome Maintenance	1	52.9×	0.031	RTEL1
SLC transporter disorders	1	51.0×	0.031	SLC4A4
HDR through Homologous Recombination (HRR)	1	47.6×	0.032	RTEL1
Disorders of transmembrane transporters	1	34.8×	0.041	SLC4A4
R-HSA-425393	1	32.4×	0.042	SLC4A4
DNA Repair	1	24.6×	0.053	RTEL1
Translation	1	15.5×	0.079	NARS2
SLC-mediated transmembrane transport	1	14.8×	0.080	SLC4A4
Cell Cycle	1	9.0×	0.124	RTEL1
Transport of small molecules	1	6.3×	0.167	SLC4A4
Disease	1	3.3×	0.293	SLC4A4
Metabolism of proteins	1	3.1×	0.296	NARS2
Metabolism	1	2.9×	0.302	RTEL1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA strand displacement	1	4213.0×	0.003	RTEL1
negative regulation of telomere maintenance in response to DNA damage	1	4213.0×	0.003	RTEL1
positive regulation of telomeric loop disassembly	1	4213.0×	0.003	RTEL1
asparaginyl-tRNA aminoacylation	1	2106.5×	0.004	NARS2
telomeric loop disassembly	1	2106.5×	0.004	RTEL1
pyramidal neuron migration to cerebral cortex	1	1404.3×	0.004	FOXG1
mitotic telomere maintenance via semi-conservative replication	1	1404.3×	0.004	RTEL1
negative regulation of t-circle formation	1	1404.3×	0.004	RTEL1
axon midline choice point recognition	1	842.6×	0.005	FOXG1
positive regulation of telomere capping	1	842.6×	0.005	RTEL1
positive regulation of telomere maintenance via telomere lengthening	1	702.2×	0.005	RTEL1
neuron fate determination	1	526.6×	0.006	FOXG1
telomere maintenance in response to DNA damage	1	468.1×	0.007	RTEL1
negative regulation of DNA recombination	1	280.9×	0.010	RTEL1
sodium ion export across plasma membrane	1	263.3×	0.010	SLC4A4
regulation of double-strand break repair via homologous recombination	1	247.8×	0.010	RTEL1
bicarbonate transport	1	200.6×	0.012	SLC4A4
positive regulation of glycolytic process	1	168.5×	0.013	SLC4A4
regulation of intracellular pH	1	150.5×	0.014	SLC4A4
positive regulation of neuroblast proliferation	1	145.3×	0.014	FOXG1
positive regulation of telomere maintenance	1	127.7×	0.015	RTEL1
positive regulation of cell cycle	1	110.9×	0.016	FOXG1
dorsal/ventral pattern formation	1	105.3×	0.016	FOXG1
replication fork processing	1	105.3×	0.016	RTEL1
neuroblast proliferation	1	91.6×	0.017	FOXG1
inner ear morphogenesis	1	75.2×	0.020	FOXG1
sodium ion transport	1	68.0×	0.021	SLC4A4
negative regulation of neuron differentiation	1	68.0×	0.021	FOXG1
telomere maintenance	1	66.9×	0.021	RTEL1
regulation of mitotic cell cycle	1	60.2×	0.022	FOXG1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
NARS2	0	0
SLC4A4	0	0
RTEL1	0	0
FOXG1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NARS2	6.1.1.22	asparagine-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	NARS2
E	Difficult family or no structure, no drug	3	SLC4A4, RTEL1, FOXG1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NARS2	0	—
SLC4A4	0	—
RTEL1	0	—
FOXG1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.