VPS33B

Chr 15AR

VPS33B late endosome and lysosome associated

Also known as: KDIDAR, PFIC12

NCBI Gene: 26276ENSG00000184056UniProt: Q9H267

Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene is a member of the Sec-1 domain family, and encodes the human ortholog of rat Vps33b which is homologous to the yeast class C Vps33 protein. The mammalian class C vacuolar protein sorting proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Mutations in this gene are associated with arthrogryposis-renal dysfunction-cholestasis syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

Primary Disease Associations & Inheritance

Arthrogryposis, renal dysfunction, and cholestasis 1MIM #208085
AR
Cholestasis, progressive familial intrahepatic, 12MIM #620010
AR
Keratoderma-ichthyosis-deafness syndrome, autosomal recessiveMIM #620009
AR
622
ClinVar variants
100
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— VPS33B
🧬
Gene-Disease Validity (ClinGen)
arthrogryposis, renal dysfunction, and cholestasis 1 · 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
100 Pathogenic / Likely Pathogenic· 250 VUS of 622 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.
0.96LOEUF
pLI 0.000
Z-score 1.76
OE 0.71 (0.53–0.96)
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.
0.36Z-score
OE missense 0.94 (0.86–1.04)
314 obs / 332.7 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.0.71 (0.53–0.96)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.86–1.04)
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.0.96
0≤1.21.6
LoF obs/exp: 31 / 43.5Missense obs/exp: 314 / 332.7Syn Z: 0.32

ClinVar Variant Classifications

622 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic65
Likely Pathogenic35
VUS250
Likely Benign185
Benign64
Conflicting23
65
Pathogenic
35
Likely Pathogenic
250
VUS
185
Likely Benign
64
Benign
23
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
15
2
48
0
65
Likely Pathogenic
22
1
11
1
35
VUS
2
206
35
7
250
Likely Benign
0
2
124
59
185
Benign
0
1
57
6
64
Conflicting
—23
Total3921227573622

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

View in ClinVar →

Protein Context — Lollipop Plot

VPS33B · protein map & ClinVar variants

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

Gene2Phenotype Curations

VPS33B-related keratoderma-ichthyosis-deafness syndrome

moderate
ARUndeterminedAltered Gene Product Structure
Skin
G2P ↗

VPS33B-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 1

MIM #208085

Molecular basis of disorder known

Autosomal recessive

Cholestasis, progressive familial intrahepatic, 12

MIM #620010

Molecular basis of disorder known

Autosomal recessive

Keratoderma-ichthyosis-deafness syndrome, autosomal recessive

MIM #620009

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
[Arthrogryposis–renal dysfunction–cholestasis syndrome].
Mikó Á et al.·Orv Hetil
2022
Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification.
Gruber R et al.·J Invest Dermatol
2017Review
VPS33B and VIPAR are essential for epidermal lamellar body biogenesis and function.
Rogerson C et al.·Biochim Biophys Acta Mol Basis Dis
2018
α-granule biogenesis: from disease to discovery.
Chen CH et al.·Platelets
2017Review
Whole-exome sequencing for genetic diagnosis of idiopathic liver injury in children.
Lülecioğlu AA et al.·J Cell Mol Med
2024
Novel VPS33B mutation in a patient with autosomal recessive keratoderma-ichthyosis-deafness syndrome.
Alter S et al.·Am J Med Genet A
2018Review
VPS33B negatively modulated by nicotine functions as a tumor suppressor in colorectal cancer.
Chen Y et al.·Int J Cancer
2020
VPS33B regulates protein sorting into and maturation of α-granule progenitor organelles in mouse megakaryocytes.
Bem D et al.·Blood
2015Functional
Vps33B is required for delivery of endocytosed cargo to lysosomes.
Galmes R et al.·Traffic
2015
VIPAS39 related arthrogryposis-renal dysfunction-cholestasis syndrome-case report and systematic review.
Kafol J et al.·Orphanet J Rare Dis
2024Case 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