VIPAS39

Chr 14AR

VPS33B interacting protein, apical-basolateral polarity regulator, spe-39 homolog

Also known as: C14orf133, SPE-39, SPE39, VIPAR, VPS16B, hSPE-39

NCBI Gene: 63894ENSG00000151445UniProt: Q9H9C1

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. Part of vesicle tethering complex. Implicated in arthrogryposis, renal dysfunction, and cholestasis 2. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

Arthrogryposis, renal dysfunction, and cholestasis 2MIM #613404
AR
393
ClinVar variants
47
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— VIPAS39
🧬
Gene-Disease Validity (ClinGen)
arthrogryposis, renal dysfunction, and cholestasis 2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
47 Pathogenic / Likely Pathogenic· 144 VUS of 393 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.80LOEUF
pLI 0.000
Z-score 2.54
OE 0.55 (0.39–0.80)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.86Z-score
OE missense 0.85 (0.77–0.95)
229 obs / 268.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.55 (0.39–0.80)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.77–0.95)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.89
0≤1.21.6
LoF obs/exp: 21 / 37.9Missense obs/exp: 229 / 268.6Syn Z: 0.86

ClinVar Variant Classifications

393 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic34
Likely Pathogenic13
VUS144
Likely Benign123
Benign50
Conflicting29
34
Pathogenic
13
Likely Pathogenic
144
VUS
123
Likely Benign
50
Benign
29
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
1
26
0
34
Likely Pathogenic
7
1
5
0
13
VUS
2
120
18
4
144
Likely Benign
1
4
77
41
123
Benign
0
0
47
3
50
Conflicting
—29
Total1712617348393

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

View in ClinVar →

Protein Context — Lollipop Plot

VIPAS39 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

VIPAS39-related arthrogryposis, renal dysfunction, and cholestasis

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Arthrogryposis, renal dysfunction, and cholestasis 2

MIM #613404

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
VIPAS39 related arthrogryposis-renal dysfunction-cholestasis syndrome-case report and systematic review.
Kafol J et al.·Orphanet J Rare Dis
2024Case report
VIPAS39 confers ferroptosis resistance in epithelial ovarian cancer through exporting ACSL4.
Jiang Y et al.·EBioMedicine
2025
Vps33b pathogenic mutations preferentially affect VIPAS39/SPE-39-positive endosomes.
Tornieri K et al.·Hum Mol Genet
2013
VPS33B and VIPAR are essential for epidermal lamellar body biogenesis and function.
Rogerson C et al.·Biochim Biophys Acta Mol Basis Dis
2018
Platelet VPS16B is dependent on VPS33B expression, as determined in two siblings with arthrogryposis, renal dysfunction, and cholestasis syndrome.
Penon-Portmann M et al.·J Thromb Haemost
2022Case report
Should any genetic defect affecting α-granules in platelets be classified as gray platelet syndrome?
Nurden AT et al.·Am J Hematol
2016Review
[Clinical features and VPS33B mutations in a family affected by arthrogryposis, renal dysfunction, and cholestasis syndrome].
Huang DG et al.·Zhongguo Dang Dai Er Ke Za Zhi
2017
Novel gene mutations in three Japanese patients with ARC syndrome associated mild phenotypes: a case series.
Satomura Y et al.·J Med Case Rep
2022Case report
Novel missense mutation in VPS33B is associated with isolated low gamma-glutamyltransferase cholestasis: Attenuated, incomplete phenotype of arthrogryposis, renal dysfunction, and cholestasis syndrome.
Qiu YL et al.·Hum Mutat
2019
One case of arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome featuring an incomplete and mild phenotype.
Yu L et al.·BMC Nephrol
2022Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools