Perrault syndrome 3

Summary

Perrault syndrome 3 (MONDO:0013588) is a disease caused by CLPP (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: CLPP (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Perrault syndrome 3
Mondo ID	MONDO:0013588
OMIM	614129
UMLS	C3808414
MedGen	814744
GARD	0015760
Is cancer (heuristic)	no

Also known as: CLPP Perrault syndrome · deafness, autosomal recessive 81 · Perrault syndrome 3 · Perrault syndrome caused by mutation in CLPP · Perrault syndrome type 3 · PRLTS3

Data availability: 22 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › Perrault syndrome › Perrault syndrome 3

Related subtypes (6): Perrault syndrome 1, Perrault syndrome 2, Perrault syndrome 4, Perrault syndrome 5, Perrault syndrome 6, Perrault syndrome 7

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

22 retrieved; paginated sample, class counts are floors:

7 likely pathogenic, 7 pathogenic, 2 benign, 2 uncertain significance, 1 benign/likely benign, 1 not provided, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2138190	NM_006012.4(CLPP):c.21del (p.Ala10fs)	CLPP	Pathogenic	criteria provided, multiple submitters, no conflicts
3257347	NM_006012.4(CLPP):c.368-2A>G	CLPP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3601032	NM_006012.4(CLPP):c.328del (p.Ser110fs)	CLPP	Pathogenic	criteria provided, single submitter
3601044	NM_006012.4(CLPP):c.661G>T (p.Glu221Ter)	CLPP	Pathogenic	criteria provided, single submitter
545503	NM_006012.4(CLPP):c.624C>G (p.Ile208Met)	CLPP	Pathogenic	no assertion criteria provided
55868	NM_006012.4(CLPP):c.433A>C (p.Thr145Pro)	CLPP	Pathogenic	no assertion criteria provided
55869	NM_006012.4(CLPP):c.440G>C (p.Cys147Ser)	CLPP	Pathogenic	no assertion criteria provided
55870	NM_006012.4(CLPP):c.270+4A>G	CLPP	Pathogenic	no assertion criteria provided
1332812	NM_006012.4(CLPP):c.299T>C (p.Ile100Thr)	CLPP	Likely pathogenic	criteria provided, single submitter
2584518	NM_006012.4(CLPP):c.484G>A (p.Gly162Ser)	CLPP	Likely pathogenic	criteria provided, single submitter
3068435	NM_006012.2(CLPP):c.-995_270+222del	CLPP	Likely pathogenic	no assertion criteria provided
3358989	NM_006012.4(CLPP):c.262A>T (p.Met88Leu)	CLPP	Likely pathogenic	criteria provided, single submitter
3601043	NM_006012.4(CLPP):c.400G>C (p.Asp134His)	CLPP	Likely pathogenic	criteria provided, single submitter
813818	NM_006012.4(CLPP):c.233G>C (p.Arg78Pro)	CLPP	Likely pathogenic	criteria provided, single submitter
869195	NM_006012.4(CLPP):c.439T>A (p.Cys147Ser)	CLPP	Likely pathogenic	no assertion criteria provided
500291	NM_006012.4(CLPP):c.173T>G (p.Leu58Arg)	CLPP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2063969	NM_006012.4(CLPP):c.791T>C (p.Val264Ala)	CLPP	Uncertain significance	criteria provided, multiple submitters, no conflicts
453066	NM_006012.4(CLPP):c.520C>T (p.Arg174Cys)	CLPP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1208030	NM_006012.4(CLPP):c.555+16G>A	CLPP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1217355	NM_006012.4(CLPP):c.199-31dup	CLPP	Benign	criteria provided, multiple submitters, no conflicts
226522	NM_006012.4(CLPP):c.-5G>A	CLPP	Benign	criteria provided, multiple submitters, no conflicts
1339862	NM_006012.4(CLPP):c.1A>G (p.Met1Val)	CLPP	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
CLPP	Definitive	Autosomal recessive	Perrault syndrome 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLPP	Orphanet:642945	Perrault syndrome type 1
CLPP	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
CLPP	HGNC:2084	ENSG00000125656	Q16740	ATP-dependent Clp protease proteolytic subunit, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLPP	ATP-dependent Clp protease proteolytic subunit, mitochondrial	Protease component of the ClpXP complex that cleaves peptides and various proteins in an ATP-dependent process.

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)
CLPP	Enzyme (other)	yes	3.4.21.92	ClpP, ClpP_Ser_AS, ClpP/TepA

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
gastrocnemius	1
hindlimb stylopod muscle	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLPP	287	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLPP	5,157

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLPP	Q16740	29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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 protein degradation	1	114.2×	0.009	CLPP

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 protein catabolic process	1	1532.0×	0.002	CLPP
membrane protein proteolysis	1	1053.2×	0.002	CLPP
protein quality control for misfolded or incompletely synthesized proteins	1	766.0×	0.002	CLPP
obsolete proteolysis involved in protein catabolic process	1	526.6×	0.002	CLPP
proteolysis	1	34.2×	0.029	CLPP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CLPP	2	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DORDAVIPRONE	3	CLPP
ONC-206	1	CLPP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CLPP	96	Binding:96

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CLPP	3.4.21.92	Endopeptidase Clp

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

2 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.

Compound	Max phase	Cohort target (bioactivity)
DORDAVIPRONE	3	CLPP
ONC-206	1	CLPP

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	1	CLPP
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.