ARPC1B
protein-codingactin related protein 2/3 complex subunit 1B, the group of WD repeat domain containing|Actin related protein 2/3 complex subunits
Gene summary
This gene encodes one of seven subunits of the human Arp2/3 protein complex. This subunit is a member of the SOP2 family of proteins and is most similar to the protein encoded by gene ARPC1A. The similarity between these two proteins suggests that they both may function as p41 subunit of the human Arp2/3 complex that has been implicated in the control of actin polymerization in cells. It is possible that the p41 subunit is involved in assembling and maintaining the structure of the Arp2/3 complex. Multiple versions of the p41 subunit may adapt the functions of the complex to different cell types or developmental stages. This protein also has a role in centrosomal homeostasis by being an activator and substrate of the Aurora A kinase. [provided by RefSeq, Mar 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~20.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0060583
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0060583
Submitter: ClinGen
ARPC1B was first reported in relation to autosomal recessive Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease in 2017 by Kahr et al. (PMID: 28368018). At least 10 loss of function (indel, deletions, duplications, nonsense) and missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 12 POINTS Variants in this gene have been reported in at least 10 probands in 4 publications (PMIDs 30254128, 28368018, 27965109, 29127144). Variants in this gene segregated with disease in 2 additional family members. More evidence is available in the literature (PMID: 30771411), but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. The mechanism for disease is expected to be homozygous loss of function (PMID: 28368018). Summary of Experimental Data: 2 POINTS This gene-disease association is supported by animal models and in vitro functional assays (PMIDs 30254128, 28368018, 27965109, 29127144). However, In summary, the ARPC1B-autosomal recessive Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease gene-disease relationship is definitive. 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 Hemostasis/Thrombosis GCEP on July 22, 2020. (SOP Version 7) Secondary Curation of ARPC1B: SCID/CID GCEP August 12, 2026 ARPC1B deficiency is an autosomal-recessive inborn error of immunity (IEI) caused by biallelic germline mutations in ARPC1B, a hematopoietically-expressed subunit of the actin-nucleating ARP2/3 complex; loss of function impairs branched actin filament formation and cytoskeletal remodeling in leukocytes and platelets. Clinically it presents as a combined immunodeficiency with early-onset recurrent (including viral) infections and thrombocytopenia with small platelets, accompanied by prominent immune dysregulation—eczema/severe dermatitis, allergy, leukocytoclastic vasculitis, and colitis. The characteristic immune phenotype includes T-cell lymphopenia with reduced naïve/CD8⁺ T cells, impaired TCR-driven proliferation and defective immune-synapse formation and cell migration, together with eosinophilia and elevated IgE and IgA. Hematopoietic cell transplantation is currently the only curative option (2019 — PMID: 30662060; 2022 — PMID: 35967303)
Inheritance Pattern: AR
Disease ID:MONDO:0060583
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic
Intervention: Allergy/Immunology/Infectious
Rationale: The condition can involve immunologic abnormalities, including immunodeficiency and vasculitis, and diagnosis may allow preventative measures and early and prompt treatment of infections (for example, with IVIG, immunosuppression, and prophylactic antibiotics); HSCT has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ARPC1B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005720.4. 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 | 1 | 1 | 101 | 2 | 105 | |
| missense | 2 | 1 | 135 | 9 | 147 | |
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 11 | 3 | 2 | 16 | ||
| splice donor/acceptor (+/-2bp) | 4 | 5 | 5 | 14 | ||
| Total | 19 | 9 | 144 | 110 | 2 | 284 |
Highest pathogenic variant AF is 0.000025312125
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005711.1 | 9 | MANE Select | |
| Ensembl | ENSP00000496599.1 | 9 | MANE Select | |
| Ensembl | ENSP00000398620.2 | 9 | Standard | |
| Ensembl | ENSP00000403324.2 | 8 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| arpc1b | Danio rerio | Structure: pro-T cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Fc gamma R-mediated phagocytosis - Homo sapiens (human)
- Salmonella infection - Homo sapiens (human)
- Endocytosis - Homo sapiens (human)
- Regulation of actin cytoskeleton - Homo sapiens (human)
- Bacterial invasion of epithelial cells - Homo sapiens (human)
Biological Process
- response to estradiol
- Arp2/3 complex-mediated actin nucleation
- Fc-gamma receptor signaling pathway involved in phagocytosis
- response to estrogen
- ephrin receptor signaling pathway
Molecular Function
- structural constituent of cytoskeleton
- protein binding
- actin filament binding
Cellular Component
- nucleus
- cytosol
- Arp2/3 protein complex
- focal adhesion
- actin cytoskeleton
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000451682
- Coding exons
- 9
- Length
- 20553
- Individuals with no LoFs
- 125724
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 24
- Defined
- 125748
- p
- 0.0000954
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.18 | 200 | 253 | 0.791 | 0.0000164 | 2444 |
| Missense (PolyPhen) | 50 | 67.451 | 0.74128 | 761 | ||
| Synonymous | 0.149 | 105 | 107 | 0.982 | 0.00000769 | 710 |
| Loss of Function | 2.75 | 7 | 20.4 | 0.343 | 0.00000107 | 203 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00011 | 0.00011 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation- promoting factor (NPF) (PubMed:11741539, PubMed:9230079). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility (PubMed:11741539, PubMed:9230079). In addition to its role in the cytoplasmic cytoskeleton, the Arp2/3 complex also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA (PubMed:29925947). The Arp2/3 complex promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs) (PubMed:29925947). {ECO:0000269|PubMed:11741539, ECO:0000269|PubMed:29925947, ECO:0000269|PubMed:9230079}.;
- Disease
- DISEASE: Platelet abnormalities with eosinophilia and immune- mediated inflammatory disease (PLTEID) [MIM:617718]: An autosomal recessive disorder characterized by platelet abnormalities, vasculitis, eosinophilia, and predisposition to inflammatory diseases. {ECO:0000269|PubMed:28368018}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.129
Intolerance Scores
- LoFtool
- 0.549
- RVIS EVS
- -0.34
- RVIS percentile EVS
- 30.56
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.822
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |