CLPP

Chr 19AR

caseinolytic mitochondrial matrix peptidase proteolytic subunit

Also known as: DFNB81, PRLTS3

NCBI Gene: 8192 ENSG00000125656 UniProt: Q16740 OMIM: 601119

The encoded protease functions as part of the mitochondrial ClpXP complex to degrade proteins and peptides in an ATP-dependent manner, serving essential housekeeping functions within mitochondria. Biallelic mutations cause Perrault syndrome 3, an autosomal recessive disorder characterized by sensorineural hearing loss in both sexes and ovarian dysgenesis in females. The gene shows significant constraint against loss-of-function variants (LOEUF 0.565), indicating intolerance to haploinsufficiency in the general population.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.561 OMIM phenotype

Clinical Summary— CLPP

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Gene-Disease Validity (ClinGen)

Perrault syndrome 3 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.57) — some intolerance to loss-of-function variants.

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ClinVar Variants

23 unique Pathogenic / Likely Pathogenic· 72 VUS of 241 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CLPP

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.56LOEUF

pLI 0.571

Z-score 2.54

OE 0.18 (0.07–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.95Z-score

OE missense 0.57 (0.48–0.68)

93 obs / 163.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.18 (0.07–0.56)

0≤0.351.4

Missense OE?0.57 (0.48–0.68)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 2 / 11.1Missense obs/exp: 93 / 163.0Syn Z: -0.52

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCLPP-related Perrault syndromeOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6552th %ile

GOF

0.4579th %ile

LOF

0.50top 25%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

241 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic11

VUS72

Likely Benign104

Benign32

Conflicting4

Pathogenic

Likely Pathogenic

VUS

104

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	3	1	0	12
Likely Pathogenic	3	7	1	0	11
VUS	0	69	1	2	72
Likely Benign	0	0	47	57	104
Benign	0	0	29	3	32
Conflicting	—				4
Total	11	79	79	62	235

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

8 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap CLPP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →