Combined oxidative phosphorylation deficiency 54

Summary

Combined oxidative phosphorylation deficiency 54 (MONDO:0030543) is a disease caused by PRORP (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PRORP (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	combined oxidative phosphorylation deficiency 54
Mondo ID	MONDO:0030543
OMIM	619737
DOID	DOID:0070427
UMLS	C5676912
MedGen	1812715
GARD	0025600
Is cancer (heuristic)	no

Also known as: COXPD54

Data availability: 15 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 54

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 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

15 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 4 pathogenic/likely pathogenic, 3 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1878501	NM_014672.4(PRORP):c.1159A>G (p.Thr387Ala)	PRORP	Pathogenic/Likely pathogenic	no assertion criteria provided
4533393	NM_014672.4(PRORP):c.893C>A (p.Ser298Ter)	PRORP	Pathogenic	no assertion criteria provided
638208	NM_014672.4(PRORP):c.1454C>T (p.Ala485Val)	PRORP	Pathogenic/Likely pathogenic	no assertion criteria provided
638209	NM_014672.4(PRORP):c.1334G>A (p.Arg445Gln)	PRORP	Pathogenic/Likely pathogenic	no assertion criteria provided
638210	NM_014672.4(PRORP):c.1197dup (p.Ser400fs)	PRORP	Pathogenic/Likely pathogenic	no assertion criteria provided
1292048	NM_014672.4(PRORP):c.1301C>A (p.Ala434Asp)	PRORP	Likely pathogenic	criteria provided, single submitter
4533392	NM_014672.4(PRORP):c.1510C>T (p.His504Tyr)	PRORP	Likely pathogenic	no assertion criteria provided
4849383	NM_014672.4(PRORP):c.1504dup (p.Arg502fs)	PRORP	Likely pathogenic	criteria provided, single submitter
1292047	NM_014672.4(PRORP):c.1235A>G (p.Asn412Ser)	PRORP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1292049	NM_014672.4(PRORP):c.1261C>T (p.Arg421Cys)	PRORP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1705405	NM_014672.4(PRORP):c.1505G>A (p.Arg502Gln)	PRORP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1878503	NM_014672.4(PRORP):c.1093T>C (p.Tyr365His)	PRORP	Uncertain significance	no assertion criteria provided
3065718	NM_014672.4(PRORP):c.934C>T (p.Gln312Ter)	PRORP	Uncertain significance	criteria provided, single submitter
3065741	NM_014672.4(PRORP):c.176del (p.Thr59fs)	PRORP	Uncertain significance	criteria provided, single submitter
1878502	NM_014672.4(PRORP):c.1241C>T (p.Ala414Val)	PRORP-PSMA6	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 2 · 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
PRORP	Strong	Autosomal recessive	combined oxidative phosphorylation deficiency 54	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRORP	Orphanet:642945	Perrault syndrome type 1
PRORP	Orphanet:642976	Perrault syndrome type 2

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
PRORP	HGNC:19958	ENSG00000100890	O15091	Mitochondrial ribonuclease P catalytic subunit	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRORP	Mitochondrial ribonuclease P catalytic subunit	Catalytic ribonuclease component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3, which cleaves tRNA molecules in their 5’-ends.

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)
PRORP	Enzyme (other)	yes	3.1.26.5	TPR-like_helical_dom_sf, PRORP_C, MRPP3_PIN_dom

Expression context

Cohort genes with no expression data: 0.

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
mucosa of transverse colon	1
primordial germ cell in gonad	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRORP	177	ubiquitous	yes	primordial germ cell in gonad, rectum, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRORP	1,894

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRORP	O15091	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
tRNA processing in the mitochondrion	1	2284.0×	0.002	PRORP
rRNA processing in the mitochondrion	1	1268.9×	0.002	PRORP
tRNA modification in the mitochondrion	1	1038.2×	0.002	PRORP
tRNA processing	1	356.9×	0.004	PRORP
rRNA processing	1	146.4×	0.008	PRORP
Metabolism of RNA	1	41.7×	0.024	PRORP

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 tRNA 5’-end processing	1	5617.3×	4e-04	PRORP
tRNA 5’-leader removal	1	1296.3×	8e-04	PRORP

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
PRORP	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRORP	3.1.26.5	ribonuclease P

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	1	PRORP
D	Druggable family + AlphaFold only, no drug	0
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)
PRORP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.