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.

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

3-methylglutaconic aciduria, type VIIA, autosomal dominantMIM #619835

3-methylglutaconic aciduria, type VIIB, autosomal recessiveMIM #616271

Neutropenia, severe congenital, 9, autosomal dominantMIM #619813

Clinical highlights

Gene–disease validity (ClinGen)

Limited · Leigh syndrome · AR · ClinGen 2020

not for standalone diagnostic reporting

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.54

LOEUF

LOF

Mechanism· G2P

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

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 48

1,013 rare PASS variants

Rare truncating (LoF)

1 in 790

151 rare PASS variants

Rare synonymous (reference)

1 in 110

287 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CLPB. 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 66	1 in 860
South Asian	~43k	1 in 55	1 in 730
Remaining (unassigned)	~30k	1 in 42	1 in 1,000
European (Finnish)	~27k	1 in 210	1 in 880
Admixed American	~22k	1 in 50	1 in 860
African / African American	~21k	1 in 63	1 in 910
East Asian	~20k	1 in 69	1 in 430
Ashkenazi Jewish	~13k	1 in 140	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 41	≈ 1 in 950

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): 16 of 16 coding exons well covered in gnomAD exomes. Genomes: 15 of 16 (exon 5 below).? see exons ↓