CLPP

protein-coding

caseinolytic mitochondrial matrix peptidase proteolytic subunit, the group of AAA ATPases

Gene summary

The protein encoded by this gene belongs to the peptidase family S14 and hydrolyzes proteins into small peptides in the presence of ATP and magnesium. The protein is transported into mitochondrial matrix and is associated with the inner mitochondrial membrane. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006012.4

Inheritance

ClinVar variants

P:25U:80B:63

Top phenotype

Perrault syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr19:6,361,427-6,370,242

External References & Databases

Ensembl (ENSG00000125656)

Transcript & Mutation Effects

hg38 • Region Span ~8.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Perrault syndrome 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013588

Submitter: ClinGen

The CLPP gene has been associated with autosomal recessive Perrault syndrome using the ClinGen Clinical Validity Framework as of 11/6/2017. This association was made using case-level data only. At least 11 missense, splice site and frameshift variants have been reported in humans. CLPP was first associated with this disease in humans as early as 2007 (Ain et al.). Association is seen in at least 11 probands in 7 publications (23541340, 27087618, 26970254, 27650058, 25956234, 27899912, 28604674). Variants in this gene segregated with disease in 13 additional family members. This gene-disease association is supported by expression studies and a null mouse model with hearing loss and infertility. In summary, CLPP is definitively associated with autosomal recessive Perrault syndrome. This classification was approved by the ClinGen Hearing Loss Working Group on 3/27/2018.

Perrault syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013588

Submitter: G2P

Perrault syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013588

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Perrault syndrome 3AR

Manifestation: Audiologic/Otolaryngologic; Endocrine; Neurologic; Obstetric

Intervention: Audiologic/Otolaryngologic; Obstetric

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Genetic knowledge may allow fertility preservation such as by storing eggs

Refs: 17690910; 22037954; 23541340

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLPP variants in ClinVar

8 Conditions Cataloged

not providedTotal: 167

Inborn genetic diseasesTotal: 36

not specifiedTotal: 25

Perrault syndrome 3Total: 22

CLPP-related disorderTotal: 19

Perrault syndromeTotal: 3

Perrault syndrome 1Total: 1

Autosomal recessive hearing impairment with normal menstrual cyclesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006012.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	58 clinvar	2 clinvar	62
missense	3 clinvar	8 clinvar	75 clinvar	3 clinvar		89
nonsense	1 clinvar					1
start loss		1 clinvar	1 clinvar			2
frameshift	6 clinvar	1 clinvar				7
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	2 clinvar			7
Total	11	14	80	61	2	168

Highest pathogenic variant AF is 0.00000982007

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006012.4	RefSeq	NP_006003.1	6	MANE Select
ENST00000245816.11	Ensembl	ENSP00000245816.3	6	MANE Select
ENST00000596149.5	Ensembl	ENSP00000472227.1	5	Standard
ENST00000596149.6	Ensembl	ENSP00000472227.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein quality control for misfolded or incompletely synthesized proteins
protein homooligomerization
proteolysis involved in cellular protein catabolic process

Molecular Function

ATP-dependent peptidase activity
serine-type endopeptidase activity
protein binding
peptidase activity
identical protein binding

Cellular Component

mitochondrion
mitochondrial matrix
endopeptidase Clp complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000245816
Coding exons: 6
Length: 7457
Individuals with no LoFs: 125377
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125380
p: 0.0000120

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.95	93	163	0.570	0.00000934	1750
Missense (PolyPhen)		22	67.928	0.32387		709
Synonymous	-0.517	75	69.5	1.08	0.00000451	564
Loss of Function	2.54	2	11.1	0.179	4.77e-7	125

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000092	0.0000088	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Protease component of the Clp complex that cleaves peptides and various proteins in an ATP-dependent process. Has low peptidase activity in the absence of CLPX. The Clp complex can degrade CSN1S1, CSN2 and CSN3, as well as synthetic peptides (in vitro) and may be responsible for a fairly general and central housekeeping function rather than for the degradation of specific substrates. {ECO:0000269|PubMed:11923310, ECO:0000269|PubMed:15522782}.;

Recessive Scores

pRec: 0.362

Intolerance Scores

LoFtool: 0.216
RVIS EVS: -0.34
RVIS percentile EVS: 30.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.922

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Low	Low
Primary Immunodeficiency	Medium	Low	Medium
Cancer	Medium	Medium	Medium