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…

Primary Disease Associations & Inheritance

Perrault syndrome 3MIM #614129

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Perrault syndrome 3 · AR · ClinGen 2018

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

259

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.56

LOEUF

Mechanism· predicted

📖

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

Background carrier burden — how many people carry a rare variant somewhere in CLPP?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

443 rare PASS variants

Rare truncating (LoF)

1 in 1,600

48 rare PASS variants

Rare synonymous (reference)

1 in 670

137 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CLPP. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 180	1 in 2,200
South Asian	~43k	1 in 130	1 in 1,700
Remaining (unassigned)	~30k	1 in 150	1 in 980
European (Finnish)	~27k	1 in 470	1 in 1,500
Admixed American	~22k	1 in 190	1 in 440
African / African American	~21k	1 in 120	≈ 1 in 7,100
East Asian	~20k	1 in 180	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 460	≈ 1 in 11,000
Middle Eastern	~2,884	1 in 140	≈ 1 in 620

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 5 of 6 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 6.? see exons ↓