Combined oxidative phosphorylation deficiency 34

Summary

Combined oxidative phosphorylation deficiency 34 (MONDO:0054741) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	combined oxidative phosphorylation deficiency 34
Mondo ID	MONDO:0054741
OMIM	617872
Orphanet	457223
DOID	DOID:0111497
UMLS	C4693450
MedGen	1631307
GARD	0017799
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation deficiency 34 · COXPD34 · syndromic sensorineural deafness due to combined oxidative phosphorylation defect · syndromic sensorineural deafness due to COXPD · syndromic sensorineural hearing loss due to COXPD

Data availability: 5 ClinVar variants · 2 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 34

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 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 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

5 retrieved; paginated sample, class counts are floors:

3 benign, 1 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
489402	NM_015971.4(MRPS7):c.550A>G (p.Met184Val)	MRPS7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029419	NM_015971.4(MRPS7):c.508-1G>A	MRPS7	Uncertain significance	criteria provided, single submitter
1263999	NM_015971.4(MRPS7):c.83+23_83+24del	GGA3	Benign	criteria provided, multiple submitters, no conflicts
379995	NM_015971.4(MRPS7):c.5C>T (p.Ala2Val)	GGA3	Benign	criteria provided, multiple submitters, no conflicts
676154	NM_015971.4(MRPS7):c.83+23C>G	GGA3	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
MRPS7	Moderate	Autosomal recessive	combined oxidative phosphorylation deficiency 34	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MRPS7	Orphanet:457223	Syndromic sensorineural deafness due to combined oxidative phosphorylation defect

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MRPS7	HGNC:14499	ENSG00000125445	Q9Y2R9	Small ribosomal subunit protein uS7m	gencc,clinvar
GGA3	HGNC:17079	ENSG00000125447	Q9NZ52	ADP-ribosylation factor-binding protein GGA3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GGA3	ADP-ribosylation factor-binding protein GGA3	Plays a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MRPS7	Other/Unknown	no		Ribosomal_uS7, Ribosomal_uS7_dom, Ribosomal_uS7_dom_sf
GGA3	Antibody/Immunoglobulin	yes		VHS_dom, GAT_dom, Clathrin_a/b/g-adaptin_app_Ig

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
gastrocnemius	1
heart left ventricle	1
granulocyte	1
pylorus	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MRPS7	289	ubiquitous	marker	gastrocnemius, apex of heart, heart left ventricle
GGA3	268	ubiquitous	marker	sural nerve, granulocyte, pylorus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MRPS7	5,544
GGA3	2,174

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPS7	Q9Y2R9	77
GGA3	Q9NZ52	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MET receptor recycling	1	571.0×	0.018	GGA3
TBC/RABGAPs	1	129.8×	0.024	GGA3
Mitochondrial translation	1	68.8×	0.024	MRPS7
Mitochondrial translation initiation	1	63.4×	0.024	MRPS7
Mitochondrial translation elongation	1	63.4×	0.024	MRPS7
Mitochondrial ribosome-associated quality control	1	61.4×	0.024	MRPS7
Mitochondrial translation termination	1	54.9×	0.024	MRPS7
Amyloid fiber formation	1	51.4×	0.024	GGA3
Translation	1	31.0×	0.036	MRPS7
Metabolism of proteins	1	6.2×	0.155	MRPS7

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of lysosomal protein catabolic process	1	1685.2×	0.008	GGA3
negative regulation of amyloid-beta formation	1	443.5×	0.009	GGA3
protein targeting to lysosome	1	312.1×	0.009	GGA3
Golgi to plasma membrane transport	1	280.9×	0.009	GGA3
Golgi to plasma membrane protein transport	1	263.3×	0.009	GGA3
protein localization to cell surface	1	247.8×	0.009	GGA3
protein destabilization	1	145.3×	0.012	GGA3
endocytic recycling	1	133.8×	0.012	GGA3
protein catabolic process	1	118.7×	0.012	GGA3
mitochondrial translation	1	86.9×	0.015	MRPS7
regulation of protein stability	1	62.9×	0.019	GGA3
translation	1	51.4×	0.021	MRPS7
intracellular protein transport	1	32.4×	0.031	GGA3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MRPS7	0	0
GGA3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MRPS7	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	GGA3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MRPS7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MRPS7	3	—
GGA3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.