VIPAS39
protein-codingVPS33B interacting protein, apical-basolateral polarity regulator, spe-39 homolog
Gene summary
Involved in endosome to lysosome transport and intracellular protein transport. Acts upstream of or within collagen metabolic process and peptidyl-lysine hydroxylation. Located in Golgi apparatus and endosome. Implicated in arthrogryposis, renal dysfunction, and cholestasis 2. [provided by Alliance of Genome Resources, Jun 2026]
- C14orf133
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~31.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013255
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013255
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0017123
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013255
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013255
Submitter: ClinGen
VIPAS39 was first reported in relation to autosomal recessive arthrogryposis, renal dysfunction, and cholestasis 2 (ARC) in 2010 (Cullinane AR, et al. ,2010, PMID: 20190753). The classical presentation of ARC includes congenital joint contractures, renal tubular dysfunction, and cholestasis. Additional features include ichthyosis, central nervous system malformation, platelet anomalies, and severe failure to thrive. At least 13 unique variants (mostly nonsense but also frameshift, splicing, start loss, and missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 9 probands in 4 publications (PMIDs: 20190753, 22753090, 23002115, 23636179). This gene-disease relationship is supported by its interaction with VPS33B (PMID: 20190753) and their function as part of a complex that interacts with an active form of RAB11A involved in apical membrane protein sorting, the alteration in mIMCD-3 cells confirming the role of VIPAS39 in regulating apical-basolateral polarity in the kidney consistent with the renal dysfunction seen in patients (PMID: 20190753), a zebrafish model recapitulating biliary abnormalities (PMID: 20190753), and a mouse model with collagen abnormalities identified in skin fibroblasts and tendons consistent with the characteristic ARC features of ichthyosis, arthrogryposis, osteopenia and bone fractures (PMID: 27435297). In summary VIPAS39 is definitively associated with autosomal recessive arthrogryposis, renal dysfunction, and cholestasis 2.
Clinical Genomic Database (CGD)
Manifestation: Gastrointestinal; Musculoskeletal; Renal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to VIPAS39 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001193315.2. 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 | 52 | 3 | 61 | ||
| missense | 1 | 124 | 12 | 137 | ||
| nonsense | 12 | 3 | 1 | 16 | ||
| start loss | 1 | 1 | ||||
| frameshift | 4 | 2 | 1 | 7 | ||
| splice donor/acceptor (+/-2bp) | 3 | 5 | 5 | 13 | ||
| Total | 20 | 11 | 136 | 65 | 3 | 235 |
Highest pathogenic variant AF is 0.000042132655
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001180244.1 | 19 | MANE Select | |
| Ensembl | ENSP00000452191.1 | 19 | MANE Select | |
| RefSeq | NP_001180243.1 | 19 | Standard | |
| RefSeq | NP_001180245.1 | 18 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| vipas39 | Danio rerio | Structure: intrahepatic bile duct Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- intracellular protein transport
- spermatogenesis
- endosome to lysosome transport
- peptidyl-lysine hydroxylation
- cell differentiation
Molecular Function
- protein binding
- protein-containing complex binding
Cellular Component
- cytoplasm
- early endosome
- late endosome
- Golgi apparatus
- HOPS complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000553888
- Coding exons
- 19
- Length
- 31278
- Individuals with no LoFs
- 125686
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 62
- Defined
- 125748
- p
- 0.000247
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.858 | 229 | 269 | 0.853 | 0.0000164 | 3235 |
| Missense (PolyPhen) | 58 | 82.516 | 0.70289 | 1052 | ||
| Synonymous | 0.857 | 87 | 97.8 | 0.890 | 0.00000535 | 908 |
| Loss of Function | 2.54 | 21 | 37.9 | 0.554 | 0.00000244 | 408 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00060 | 0.00060 | rare |
| East Asian | 0.00027 | 0.00027 | rare |
| Finnish | 0.00074 | 0.00074 | rare |
| European (Non-Finnish) | 0.00018 | 0.00018 | rare |
| South Asian | 0.00033 | 0.00033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Proposed to be involved in endosomal maturation implicating in part VPS33B. In epithelial cells, the VPS33B:VIPAS39 complex may play a role in the apical RAB11A- dependent recycling pathway and in the maintenance of the apical- basolateral polarity (PubMed:20190753). May play a role in lysosomal trafficking, probably via association with the core HOPS complex in a discrete population of endosomes; the functions seems to be indepenedent of VPS33B (PubMed:19109425). May play a role in vesicular trafficking during spermatogenesis (By similarity). May be involved in direct or indirect transcriptional regulation of E- cadherin (By similarity). {ECO:0000250|UniProtKB:Q23288, ECO:0000269|PubMed:19109425, ECO:0000269|PubMed:20190753}.;
- Disease
- DISEASE: Arthrogryposis, renal dysfunction and cholestasis syndrome 2 (ARCS2) [MIM:613404]: A multisystem disorder, characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase activity. Platelet dysfunction is common. Note=The disease is caused by mutations affecting the gene represented in this entry. In liver, CEACAM5 and ABCB11 are mislocalized and E-cadherin expression is decreased.;
Recessive Scores
- pRec
- 0.119
Intolerance Scores
- RVIS EVS
- -0.4
- RVIS percentile EVS
- 26.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |