CLPB

Chr 11ADAR

ClpB family mitochondrial disaggregase

Also known as: ANKCLB, ANKCLP, HSP78, MEGCANN, MGCA7, MGCA7A, SCN9, SKD3

NCBI Gene: 81570ENSG00000162129UniProt: Q9H078

This gene belongs to the ATP-ases associated with diverse cellular activities (AAA+) superfamily. Members of this superfamily form ring-shaped homo-hexamers and have highly conserved ATPase domains that are involved in various processes including DNA replication, protein degradation and reactivation of misfolded proteins. All members of this family hydrolyze ATP through their AAA+ domains and use the energy generated through ATP hydrolysis to exert mechanical force on their substrates. In addition to an AAA+ domain, the protein encoded by this gene contains a C-terminal D2 domain, which is characteristic of the AAA+ subfamily of Caseinolytic peptidases to which this protein belongs. It cooperates with Hsp70 in the disaggregation of protein aggregates. Allelic variants of this gene are associated with 3-methylglutaconic aciduria, which causes cataracts and neutropenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

Primary Disease Associations & Inheritance

3-methylglutaconic aciduria, type VIIA, autosomal dominantMIM #619835
AD
3-methylglutaconic aciduria, type VIIB, autosomal recessiveMIM #616271
AR
Neutropenia, severe congenital, 9, autosomal dominantMIM #619813
AD
580
ClinVar variants
45
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— CLPB
🧬
Gene-Disease Validity (ClinGen)
Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
45 Pathogenic / Likely Pathogenic· 289 VUS of 580 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.54LOEUF
pLI 0.000
Z-score 3.81
OE 0.34 (0.22–0.54)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.05Z-score
OE missense 0.86 (0.79–0.94)
378 obs / 440.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.34 (0.22–0.54)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.79–0.94)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.88
0≤1.21.6
LoF obs/exp: 13 / 38.5Missense obs/exp: 378 / 440.1Syn Z: 1.21

ClinVar Variant Classifications

580 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31
Likely Pathogenic14
VUS289
Likely Benign217
Benign13
Conflicting16
31
Pathogenic
14
Likely Pathogenic
289
VUS
217
Likely Benign
13
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
9
15
0
31
Likely Pathogenic
8
3
3
0
14
VUS
4
257
26
2
289
Likely Benign
0
17
110
90
217
Benign
0
1
10
2
13
Conflicting
—16
Total1928716494580

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

View in ClinVar →

Protein Context — Lollipop Plot

CLPB · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CLPB-related 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

3-methylglutaconic aciduria, type VIIA, autosomal dominant

MIM #619835

Molecular basis of disorder known

Autosomal dominant

3-methylglutaconic aciduria, type VIIB, autosomal recessive

MIM #616271

Molecular basis of disorder known

Autosomal recessive

Neutropenia, severe congenital, 9, autosomal dominant

MIM #619813

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — CLPB
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The Probiotic Strain H. alvei HA4597(®) Improves Weight Loss in Overweight Subjects under Moderate Hypocaloric Diet: A Proof-of-Concept, Multicenter Randomized, Double-Blind Placebo-Controlled Study.
Déchelotte P et al.·Nutrients
2021
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
The Bacterial ClpXP-ClpB Family Is Enriched with RNA-Binding Protein Complexes.
Auburger G et al.·Cells
2022Review
CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex.
Baker MJ et al.·J Cell Biol
2024Functional
Mitochondrial Protein Homeostasis and Cardiomyopathy.
Wachoski-Dark E et al.·Int J Mol Sci
2022Review
Hsp100 Molecular Chaperone ClpB and Its Role in Virulence of Bacterial Pathogens.
Kędzierska-Mieszkowska S et al.·Int J Mol Sci
2021Review
Discerning clinicopathological features of congenital neutropenia syndromes: an approach to diagnostically challenging differential diagnoses.
Parisi X et al.·J Clin Pathol
2024Review
AAA+ Molecular Chaperone ClpB in Leptospira interrogans: Its Role and Significance in Leptospiral Virulence and Pathogenesis of Leptospirosis.
Kędzierska-Mieszkowska S et al.·Int J Mol Sci
2020Review
Plasma enterobacterial ClpB levels and ClpB- and α-MSH-reactive immunoglobulins in lung cancer patients with and without anorexia.
Molfino A et al.·Nutrition
2020Cohort
Biochemical characterization of ClpB and DnaK from Anaplasma phagocytophilum.
Ranaweera CB et al.·Cell Stress Chaperones
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools