CLPP

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

Basic information

Region (hg38): 19:6361427-6370242

Links

ENSG00000125656 ∙ NCBI:8192 ∙ OMIM:601119 ∙ HGNC:2084 ∙ Uniprot:Q16740 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Perrault syndrome 3 (Strong), mode of inheritance: AR
• Perrault syndrome 3 (Strong), mode of inheritance: AR
• Perrault syndrome (Supportive), mode of inheritance: AR
• Perrault syndrome 3 (Definitive), mode of inheritance: AR
• Perrault syndrome (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Perrault syndrome 3	AR	Audiologic/Otolaryngologic; Obstetric	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	Audiologic/Otolaryngologic; Endocrine; Neurologic; Obstetric	17690910; 22037954; 23541340

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CLPP gene.

• not provided (5 variants)
• Perrault syndrome 3 (3 variants)
• Perrault syndrome 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CLPP gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	47	3	51
missense		5	52			57
nonsense	1					1
start loss						0
frameshift	6					6
inframe indel						0
splice donor/acceptor (+/-2bp)	1	2				3
splice region			2	7	1	10
non coding				37	21	58
Total	8	7	53	84	24

Highest pathogenic variant AF is 0.0000131

Variants in CLPP

This is a list of pathogenic ClinVar variants found in the CLPP region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-6361567-G-GCC		not specified	Likely benign (Jan 30, 2018)
19-6361570-G-A		not specified • Perrault syndrome 3	Benign (Jul 22, 2021)
19-6361575-A-G		Perrault syndrome 3	not provided (-)
19-6361578-T-TGGCCCGGAATATTGGTAGGGGG			Pathogenic (Sep 27, 2022)
19-6361583-C-T			Likely benign (Feb 08, 2024)
19-6361585-G-A		Inborn genetic diseases	Uncertain significance (Feb 15, 2023)
19-6361589-A-G		not specified	Conflicting classifications of pathogenicity (Apr 15, 2023)
19-6361592-G-A			Likely benign (Dec 22, 2023)
19-6361594-TA-T		Perrault syndrome 3	Pathogenic (Apr 30, 2022)
19-6361595-A-G			Likely benign (Aug 18, 2022)
19-6361597-G-C			Uncertain significance (Jan 19, 2024)
19-6361597-G-T			Uncertain significance (Aug 23, 2022)
19-6361602-G-T			Uncertain significance (Oct 13, 2023)
19-6361603-C-G			Uncertain significance (Feb 13, 2023)
19-6361604-C-G			Likely benign (Jan 06, 2024)
19-6361605-C-T		Inborn genetic diseases	Uncertain significance (Apr 25, 2022)
19-6361607-G-A			Likely benign (Nov 05, 2024)
19-6361613-G-A		not specified	Likely benign (Jul 24, 2024)
19-6361613-G-T			Likely benign (Oct 25, 2022)
19-6361616-A-C		not specified	Likely benign (Dec 26, 2020)
19-6361617-T-C			Uncertain significance (Feb 15, 2023)
19-6361634-G-A			Likely benign (Jun 12, 2022)
19-6361659-C-T			Uncertain significance (Mar 08, 2022)
19-6361660-C-T		Inborn genetic diseases	Uncertain significance (Apr 08, 2024)
19-6361667-G-T			Uncertain significance (Mar 01, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CLPP	protein_coding	protein_coding	ENST00000245816	6	7457

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.571	0.427	125377	0	3	125380	0.0000120

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.95	93	163	0.570	0.00000934	1750
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000298	0.0000298
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000919	0.00000883
Middle Eastern	0.00	0.00
South Asian	0.0000329	0.0000327
Other	0.00	0.00

dbNSFP

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

Haploinsufficiency Scores

• pHI: 0.176
• hipred: Y
• hipred_score: 0.599
• ghis: 0.613

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.922

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Clpp
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); immune system phenotype; skeleton phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; embryo phenotype

Gene ontology

• Biological process: protein quality control for misfolded or incompletely synthesized proteins;protein homooligomerization;proteolysis involved in cellular protein catabolic process
• Cellular component: mitochondrion;mitochondrial matrix;endopeptidase Clp complex
• Molecular function: ATP-dependent peptidase activity;serine-type endopeptidase activity;protein binding;peptidase activity;identical protein binding;ATPase binding