Combined oxidative phosphorylation deficiency 39

Summary

Combined oxidative phosphorylation deficiency 39 (MONDO:0032726) is a disease caused by GFM2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GFM2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 30
• Phenotypes (HPO): 52

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

52 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000543	Optic disc pallor	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000817	Reduced eye contact	Frequent (30-79%)
HP:0001273	Abnormal corpus callosum morphology	Frequent (30-79%)
HP:0001317	Abnormal cerebellum morphology	Frequent (30-79%)
HP:0001321	Cerebellar hypoplasia	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0001662	Bradycardia	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0002490	Increased CSF lactate	Frequent (30-79%)
HP:0002500	Abnormal cerebral white matter morphology	Frequent (30-79%)
HP:0002505	Loss of ambulation	Frequent (30-79%)
HP:0007321	Deep white matter hypodensities	Frequent (30-79%)
HP:0008763	No social interaction	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0012379	Abnormal enzyme/coenzyme activity	Frequent (30-79%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)
HP:0004305	Involuntary movements	Occasional (5-29%)
HP:0005745	Congenital foot contractures	Occasional (5-29%)
HP:0006956	Dilation of lateral ventricles	Occasional (5-29%)
HP:0007366	Atrophy/Degeneration affecting the brainstem	Occasional (5-29%)
HP:0007371	Corpus callosum atrophy	Occasional (5-29%)
HP:0011448	Ankle clonus	Occasional (5-29%)
HP:0011470	Nasogastric tube feeding in infancy	Occasional (5-29%)
HP:0012428	Prominent calcaneus	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)
HP:0031959	Leg dystonia	Occasional (5-29%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000194	Open mouth	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000762	Decreased nerve conduction velocity	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0001998	Neonatal hypoglycemia	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002058	Myopathic facies	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002061	Lower limb spasticity	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002151	Increased circulating lactate concentration	Occasional (5-29%)
HP:0002307	Drooling	Occasional (5-29%)
HP:0002353	EEG abnormality	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	combined oxidative phosphorylation deficiency 39
Mondo ID	MONDO:0032726
OMIM	618397
Orphanet	565624
DOID	DOID:0111475
UMLS	C5193075
MedGen	1683958
GARD	0017999
Is cancer (heuristic)	no

Also known as: COXPD39

Data availability: 30 ClinVar variants · 4 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 deficiency 39

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 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 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

30 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 6 likely pathogenic, 4 pathogenic, 3 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012511	NM_032380.5(GFM2):c.1321-1G>A	GFM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225205	NM_032380.5(GFM2):c.206+4A>G	GFM2	Pathogenic	no assertion criteria provided
225206	NM_032380.5(GFM2):c.2029-1G>A	GFM2	Pathogenic	no assertion criteria provided
440787	NM_032380.5(GFM2):c.636del (p.Glu213fs)	GFM2	Pathogenic	no assertion criteria provided
440788	NM_032380.5(GFM2):c.275A>C (p.Tyr92Ser)	GFM2	Pathogenic	no assertion criteria provided
2444250	NM_032380.5(GFM2):c.304+1G>A	GFM2	Likely pathogenic	criteria provided, single submitter
3234858	NM_032380.5(GFM2):c.1833dup (p.Ala612fs)	GFM2	Likely pathogenic	criteria provided, single submitter
4056493	NM_032380.5(GFM2):c.1113del (p.Phe372fs)	GFM2	Likely pathogenic	criteria provided, single submitter
4277858	NM_032380.5(GFM2):c.2028+1G>A	GFM2	Likely pathogenic	criteria provided, single submitter
4292341	NM_032380.5(GFM2):c.1400del (p.Lys467fs)	GFM2	Likely pathogenic	criteria provided, single submitter
4845765	NM_032380.5(GFM2):c.349C>T (p.Arg117Ter)	GFM2	Likely pathogenic	criteria provided, single submitter
214509	NM_032380.5(GFM2):c.569G>A (p.Arg190Gln)	GFM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
390399	NM_032380.5(GFM2):c.431-3T>C	GFM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
55856	NM_032380.5(GFM2):c.1728T>A (p.Asp576Glu)	GFM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030025	NM_032380.5(GFM2):c.200T>C (p.Ile67Thr)	GFM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1236174	NM_032380.5(GFM2):c.461G>A (p.Arg154Gln)	GFM2	Uncertain significance	criteria provided, single submitter
1698268	NM_032380.5(GFM2):c.2231G>A (p.Arg744Gln)	GFM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805680	NM_032380.5(GFM2):c.1758G>C (p.Arg586Ser)	GFM2	Uncertain significance	criteria provided, single submitter
1899967	NM_032380.5(GFM2):c.1615C>A (p.His539Asn)	GFM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1933031	NM_032380.5(GFM2):c.1642A>G (p.Lys548Glu)	GFM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
214510	NM_032380.5(GFM2):c.1040T>C (p.Met347Thr)	GFM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
214513	NM_032380.5(GFM2):c.1229T>A (p.Ile410Lys)	GFM2	Uncertain significance	criteria provided, single submitter
214516	NM_032380.5(GFM2):c.1984T>A (p.Ser662Thr)	GFM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
214521	NM_032380.5(GFM2):c.64-16_64-3del	GFM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2413137	NM_032380.5(GFM2):c.1124T>C (p.Leu375Pro)	GFM2	Uncertain significance	criteria provided, single submitter
2413138	NM_032380.5(GFM2):c.240T>G (p.Asp80Glu)	GFM2	Uncertain significance	criteria provided, single submitter
2432118	NM_032380.5(GFM2):c.2164C>T (p.Gln722Ter)	GFM2	Uncertain significance	criteria provided, single submitter
2442098	NM_032380.5(GFM2):c.2206A>G (p.Ile736Val)	GFM2	Uncertain significance	criteria provided, single submitter
137476	NM_032380.5(GFM2):c.1718G>A (p.Arg573His)	GFM2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
137478	NM_032380.5(GFM2):c.43A>G (p.Ile15Val)	GFM2	Benign/Likely benign	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
GFM2	Strong	Autosomal recessive	combined oxidative phosphorylation deficiency 39	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GFM2	Orphanet:565624	Combined oxidative phosphorylation defect type 39

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
GFM2	HGNC:29682	ENSG00000164347	Q969S9	Ribosome-releasing factor 2, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GFM2	Ribosome-releasing factor 2, mitochondrial	Mitochondrial GTPase that mediates the disassembly of ribosomes from messenger RNA at the termination of mitochondrial protein biosynthesis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GFM2	Other/Unknown	no		EFG_V-like, T_Tr_GTP-bd_dom, Small_GTP-bd

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
bronchial epithelial cell	1
left ventricle myocardium	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GFM2	262	ubiquitous	marker	left ventricle myocardium, tibialis anterior, bronchial epithelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GFM2	1,997

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GFM2	Q969S9	2

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 translation	1	137.6×	0.018	GFM2
Mitochondrial translation termination	1	109.8×	0.018	GFM2
Translation	1	62.1×	0.021	GFM2
Metabolism of proteins	1	12.4×	0.081	GFM2

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
mitochondrial translational termination	1	3370.4×	9e-04	GFM2
ribosome disassembly	1	991.3×	0.002	GFM2
mitochondrial translation	1	173.7×	0.006	GFM2

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
GFM2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	1	GFM2

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)
GFM2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.