CLPB

Chr 11ADAR

ClpB family mitochondrial disaggregase

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

NCBI Gene: 81570 ENSG00000162129 UniProt: Q9H078 OMIM: 616254

This protein functions as an ATP-dependent disaggregase that maintains mitochondrial protein solubility and plays a role in granulocyte differentiation. Mutations cause 3-methylglutaconic aciduria with cataracts and neutropenia, as well as severe congenital neutropenia, with both autosomal dominant and autosomal recessive inheritance patterns described. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.536), reflecting its tolerance to certain types of mutations while still causing disease.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.543 OMIM phenotypes

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

55 unique Pathogenic / Likely Pathogenic· 440 VUS of 896 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — CLPB

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.54LOEUF

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?

1.05Z-score

OE missense 0.86 (0.79–0.94)

378 obs / 440.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.22–0.54)

0≤0.351.4

Missense OE?0.86 (0.79–0.94)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 13 / 38.5Missense obs/exp: 378 / 440.1Syn Z: 1.21

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCLPB-related 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropeniaLOFAR

This gene — mechanism propensity

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

0.6839th %ile

GOF

0.5563th %ile

LOF

0.3939th %ile

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.

Literature Evidence

DNIn each individual, we identified one of four different de novo monoallelic missense variants in CLPB. We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 34140661 ↗

ClinVar Variant Classifications

896 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34

Likely Pathogenic21

VUS440

Likely Benign323

Benign30

Conflicting26

Pathogenic

Likely Pathogenic

440

VUS

323

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	19	8	7	0	34
Likely Pathogenic	16	4	1	0	21
VUS	8	399	27	6	440
Likely Benign	1	29	150	143	323
Benign	0	1	27	2	30
Conflicting	—				26
Total	44	441	212	151	874

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap CLPB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →