RBCK1
protein-codingRANBP2-type and C3HC4-type zinc finger containing 1, the group of Linear ubiquitin chain assembly complex |RBR E3 ubiquitin ligases|Ring finger proteins|Zinc fingers RANBP2-type
Gene summary
Enables several functions, including identical protein binding activity; transcription coactivator activity; and ubiquitin binding activity. Involved in several processes, including T cell receptor signaling pathway; positive regulation of canonical NF-kappaB signal transduction; and protein linear polyubiquitination. Part of LUBAC complex. Implicated in glycogen storage disease. [provided by Alliance of Genome Resources, Jun 2026]
- C20orf18
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~24.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014389
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0018348
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0017992
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014389
Submitter: ClinGen
*RBCK1* (HOIL-1) was first reported in relation to autosomal recessive polyglucosan body myopathy 1 (PGBM1) with or without immunodeficiency in 2012 (Boisson et al., PMID: 23104095). RBCK1 is a part of the LUBAC complex and therefore has a role in NF-kappaB signaling. It is also important in myogenesis, as it is enriched in fast-twitch glycolytic muscle fibers. PGBM1 is characterized by a variable phenotype spectrum, with onset often during childhood though it can be much later in life. The majority of patients present with progressive proximal muscle weakness, resulting in difficulties in ambulation. Many patients develop progressive dilated cardiomyopathy, and a subset present with severe immunodeficiency. 7 unique variants (6 frameshifts leading to early stop, 1 stop-gain) that have been reported in 7 probands in 5 publications (PMIDs: 29260357, 38588043, 23104095, 38922716, 32187699) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function (PMIDs: 29260357, 38588043, 23104095, 38922716, 32187699). This gene-disease relationship is also supported by animal models and in vitro functional assays. (PMIDs: 25599590, 23104095, ). Specifically, knockout mouse models with abrogated *Rbck1* expression presented with features of human disease, including increased susceptibility to certain infections and increased PAS-positive deposits (PMID: 25599590). Immortalized patient cells with early stop variants demonstrated impaired NF-kappaB-dependent responses to TNFR families, which aligns with the susceptibility of these patients to invasive pyogenic bacterial disease (PMID: 23104095). In summary, there is definitive evidence supporting the relationship between *RBCK1* and autosomal recessive polyglucosan body myopathy 1 (PGBM1) with or without immunodeficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date May 21st, 2026 (SOP Version 12).
Inheritance Pattern: AR
Disease ID:MONDO:0014389
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0014389
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014389
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Musculoskeletal; Neurologic
Intervention: Allergy/Immunology/Infectious; Cardiovascular
Rationale: Individuals have been described as being affected by recurrent and severe infections, and awareness may allow surveillance, prophylactic measures, and early and aggressive management of infections; Progressive dilated cardiomyopathy necessitating heart transplant has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RBCK1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_031229.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 6 | 169 | 3 | 178 | ||
| missense | 3 | 189 | 8 | 200 | ||
| nonsense | 13 | 4 | 17 | |||
| start loss | 1 | 1 | ||||
| frameshift | 17 | 11 | 28 | |||
| splice donor/acceptor (+/-2bp) | 1 | 6 | 3 | 10 | ||
| Total | 31 | 24 | 199 | 177 | 3 | 434 |
Highest pathogenic variant AF is 0.000016109525
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_112506.2 | 12 | MANE Select | |
| Ensembl | ENSP00000348632.6 | 12 | MANE Select | |
| RefSeq | NP_001310885.1 | 8 | Standard | |
| RefSeq | NP_001310887.1 | 8 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| rbck1 | Danio rerio | Structure: pharyngeal arch Quality: disorganized abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Necroptosis - Homo sapiens (human)
- NOD-like receptor signaling pathway - Homo sapiens (human)
- Regulation of toll-like receptor signaling pathway
- Signal Transduction
- Immune System
Biological Process
- protein polyubiquitination
- I-kappaB kinase/NF-kappaB signaling
- regulation of tumor necrosis factor-mediated signaling pathway
- viral process
- negative regulation of NF-kappaB transcription factor activity
Molecular Function
- ubiquitin-protein transferase activity
- protein binding
- identical protein binding
- ubiquitin binding
- metal ion binding
Cellular Component
- cytosol
- LUBAC complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000356286
- Coding exons
- 12
- Length
- 23469
- Individuals with no LoFs
- 125730
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 18
- Defined
- 125748
- p
- 0.0000716
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.00 | 227 | 329 | 0.689 | 0.0000217 | 3293 |
| Missense (PolyPhen) | 28 | 83.505 | 0.33531 | 880 | ||
| Synonymous | 0.254 | 133 | 137 | 0.972 | 0.00000927 | 985 |
| Loss of Function | 3.92 | 8 | 31.9 | 0.251 | 0.00000172 | 315 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.000054 | 0.000053 | rare |
| South Asian | 0.00017 | 0.00016 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, such as UBE2L3/UBCM4, and then transfers it to substrates. Functions as an E3 ligase for oxidized IREB2 and both heme and oxygen are necessary for IREB2 ubiquitination. Promotes ubiquitination of TAB2 and IRF3 and their degradation by the proteasome. Component of the LUBAC complex which conjugates linear ('Met-1'-linked) polyubiquitin chains to substrates and plays a key role in NF- kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex. Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis. Binds polyubiquitin of different linkage types. {ECO:0000269|PubMed:12629548, ECO:0000269|PubMed:17006537, ECO:0000269|PubMed:17449468, ECO:0000269|PubMed:18711448, ECO:0000269|PubMed:19136968, ECO:0000269|PubMed:20005846, ECO:0000269|PubMed:21455173, ECO:0000269|PubMed:21455180, ECO:0000269|PubMed:21455181}.;
- Disease
- DISEASE: Polyglucosan body myopathy 1 with or without immunodeficiency (PGBM1) [MIM:615895]: A disease characterized by polyglucosan storage myopathy associated with early-onset progressive muscle weakness and progressive dilated cardiomyopathy, which may necessitate cardiac transplant in severe cases. Some patients present with severe immunodeficiency, invasive bacterial infections and chronic autoinflammation. {ECO:0000269|PubMed:23104095, ECO:0000269|PubMed:23798481}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.116
Intolerance Scores
- LoFtool
- 0.524
- RVIS EVS
- -0.91
- RVIS percentile EVS
- 9.9
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.947
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |