VPS33B

Summary

VPS33B (VPS33B late endosome and lysosome associated, HGNC:12712) is a protein-coding gene on chromosome 15q26.1, encoding Vacuolar protein sorting-associated protein 33B (Q9H267). May play a role in vesicle-mediated protein trafficking to lysosomal compartments and in membrane docking/fusion reactions of late endosomes/lysosomes.

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.

Source: NCBI Gene 26276 — RefSeq curated summary.

At a glance

• Gene–disease (curated): arthrogryposis, renal dysfunction, and cholestasis 1 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 605 total — 30 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 77
• MANE Select transcript: NM_018668

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12712
Approved symbol	VPS33B
Name	VPS33B late endosome and lysosome associated
Location	15q26.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ14848
Ensembl gene	ENSG00000184056
Ensembl biotype	protein_coding
OMIM	608552
Entrez	26276

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 9 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000333371, ENST00000535906, ENST00000554264, ENST00000554660, ENST00000556096, ENST00000557358, ENST00000557470, ENST00000574755, ENST00000853125, ENST00000853126, ENST00000853127, ENST00000940924, ENST00000940925, ENST00000940926, ENST00000940927

RefSeq mRNA: 3 — MANE Select: NM_018668 NM_001289148, NM_001289149, NM_018668

CCDS: CCDS10369, CCDS73783

Canonical transcript exons

ENST00000333371 — 23 exons

Exon	Start	End
ENSE00001305570	90998673	90999054
ENSE00003476456	91006652	91006729
ENSE00003500164	91000490	91000591
ENSE00003503191	90999900	90999975
ENSE00003543676	91017805	91017885
ENSE00003548605	91006372	91006445
ENSE00003549355	91007870	91007964
ENSE00003576325	91013804	91013871
ENSE00003583228	91001389	91001462
ENSE00003589315	91005694	91005784
ENSE00003590149	91014384	91014433
ENSE00003610527	91022154	91022594
ENSE00003611875	91002050	91002182
ENSE00003616112	90999677	90999793
ENSE00003624584	91005380	91005454
ENSE00003630384	91004877	91004931
ENSE00003630850	91016963	91017024
ENSE00003634268	91005973	91006059
ENSE00003638716	91007469	91007573
ENSE00003643119	91006950	91007046
ENSE00003664917	91009801	91009846
ENSE00003670105	91005055	91005119
ENSE00003693543	91003085	91003131

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 95.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.2072 / max 83.3943, expressed in 1769 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151596	6.6931	1762
151595	0.5141	287

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	95.50	gold quality
Brodmann (1909) area 23	UBERON:0013554	91.33	gold quality
middle temporal gyrus	UBERON:0002771	91.12	gold quality
amniotic fluid	UBERON:0000173	90.56	gold quality
endothelial cell	CL:0000115	90.33	gold quality
lower esophagus mucosa	UBERON:0035834	89.61	gold quality
primary visual cortex	UBERON:0002436	89.01	gold quality
gingival epithelium	UBERON:0001949	88.81	gold quality
cerebellar hemisphere	UBERON:0002245	88.49	gold quality
cerebellar cortex	UBERON:0002129	88.44	gold quality
esophagus squamous epithelium	UBERON:0006920	88.41	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.36	gold quality
pigmented layer of retina	UBERON:0001782	87.82	gold quality
granulocyte	CL:0000094	87.64	gold quality
cerebellum	UBERON:0002037	87.60	gold quality
squamous epithelium	UBERON:0006914	87.58	gold quality
epithelium of esophagus	UBERON:0001976	87.28	gold quality
prefrontal cortex	UBERON:0000451	87.11	gold quality
mucosa of transverse colon	UBERON:0004991	87.11	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.88	gold quality
palpebral conjunctiva	UBERON:0001812	86.74	gold quality
skin of leg	UBERON:0001511	86.73	gold quality
adenohypophysis	UBERON:0002196	86.38	gold quality
occipital lobe	UBERON:0002021	86.32	gold quality
right frontal lobe	UBERON:0002810	86.28	gold quality
skin of abdomen	UBERON:0001416	86.26	gold quality
spleen	UBERON:0002106	85.82	gold quality
frontal cortex	UBERON:0001870	85.77	gold quality
neocortex	UBERON:0001950	85.76	gold quality
zone of skin	UBERON:0000014	85.68	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6058	no	73.86
E-ANND-3	no	3.99

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT1

miRNA regulators (miRDB)

35 targeting VPS33B, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-605-5P	98.79	68.24	1161
HSA-MIR-374B-3P	98.63	68.24	1360
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-3188	98.58	65.60	878
HSA-MIR-2117	98.48	67.97	1307
HSA-MIR-4536-5P	98.47	64.39	657
HSA-MIR-1304-3P	98.29	66.44	1207
HSA-MIR-4469	97.93	65.81	1319
HSA-MIR-503-5P	97.87	66.83	575
HSA-MIR-510-5P	97.66	65.82	916

Literature-anchored findings (GeneRIF, showing 25)

• encodes a homolog of the class C yeast vacuolar protein sorting gene, that contains a Sec1-like domain important in the regulation of vesicle-to-target SNARE complex formation and subsequent membrane fusion (PMID:15052268)
• A and B classes reflect the evolution of organelle/tissue-specific functions (PMID:15790593)
• VPS33B is involved in intracellular vesicle trafficking (PMID:16123220)
• The present observations indicate that VPS33B deficiency results in abnormal secretion of lamellar granules, which underlies ichthyosis in ARC syndrome. (PMID:18347289)
• Genetic deletion of ptpA attenuates Mycobacterium tuberculosis growth in human macrophages and identify VPS33B, a regulator of membrane fusion, as a PtpA substrate. (PMID:18474358)
• We assessed the clinical characteristics and investigated the VPS33B mutations in Korean patients with ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome. (PMID:19274792)
• SPE-39 due to tyrosine phosphorylation and ubiquitination on the function of Vps33B in the EGF-stimulated cells (PMID:22677173)
• Evidence of genotype-phenotype correlation in ARC syndrome the VPS33B c.1225+5G>C mutation predicts a mild phenotype. (PMID:22753090)
• VPS16B, similar to its binding partner VPS33B, is essential for megakaryocyte and platelet alpha-granule biogenesis. (PMID:23002115)
• Our data suggest that the ARC syndrome may result through impaired VIPAS39/SPE-39 and Vps33b-dependent endosomal maturation or fusion. (PMID:23918659)
• Case Report: novel mutations in VPS33B in Chinese patient with arthrogryposis, renal dysfunction and cholestasis syndrome. (PMID:24415890)
• Case Report: neonate with ARC syndrome and high GGT cholestasis caused by VPS33B heterozygous mutations. (PMID:24782640)
• Novel splice site mutations in the VPS33B gene were identified in arthrogryposis, renal dysfunction, and cholestasis syndrome in Koreans. (PMID:24917129)
• Abnormal protein trafficking and impairment in multivesicular bodies maturation in Megakaryocytes underlie the alpha-granule deficiency in Vps33b(fl/fl)-ER(T2) mouse and ARC patients. (PMID:25947942)
• Vesicular trafficking complexes, containing VPS33B, are a novel class of modifiers of integrin function. (PMID:26399659)
• ARKID syndrome is caused by VPS33B mutation. (PMID:28017832)
• Down-regulation of Vps33b expression is a critical step for inflammation-driven hepatocellular carcinoma, and Vps33b serves as an important tumor suppressor in hepatocarcinogenesis. (PMID:29729199)
• VPS33B is negatively regulated by LMP-1 and nicotine and thus suppresses the proliferation of nasopharyngeal carcinoma (NPC) cells by interacting with NESG1 to regulate EGFR/PI3K/AKT/c-Myc/P53/miR-133a-3p signaling in NPC cells. (PMID:30944308)
• NESG1 also activated VPS33B expression via the RAS/ERK/c-Jun pathway. (PMID:31125123)
• Results found VPS33B variation c.1726T>C, p.Cys576Arg to be associated with the attenuated phenotype of arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome. (PMID:31479177)
• Mechanism of platelet alpha-granule biogenesis: study of cargo transport and the VPS33B-VPS16B complex in a model system. (PMID:31501156)
• VPS33B interacts with NESG1 to suppress cell growth and cisplatin chemoresistance in ovarian cancer. (PMID:33788346)
• Syntaxin 12 and COMMD3 are new factors that function with VPS33B in the biogenesis of platelet alpha-granules. (PMID:34905616)
• Mucopolysaccharidosis-Plus Syndrome: Report on a Polish Patient with a Novel VPS33A Variant with Comparison with Other Described Patients. (PMID:36232726)
• The Sec1-Munc18 protein VPS33B forms a uniquely bidirectional complex with VPS16B. (PMID:37062417)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	vps33b	ENSDARG00000044813
mus_musculus	Vps33b	ENSMUSG00000030534
rattus_norvegicus	Vps33b	ENSRNOG00000013149
drosophila_melanogaster	Vps33B	FBGN0039335
caenorhabditis_elegans		WBGENE00016960

Paralogs (7): STXBP2 (ENSG00000076944), SCFD1 (ENSG00000092108), STXBP3 (ENSG00000116266), VPS45 (ENSG00000136631), STXBP1 (ENSG00000136854), VPS33A (ENSG00000139719), SCFD2 (ENSG00000184178)

Protein

Protein identifiers

Vacuolar protein sorting-associated protein 33B — Q9H267 (reviewed: Q9H267)

All UniProt accessions (4): A0A0S2Z577, Q9H267, F5H008, G3V3F9

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in vesicle-mediated protein trafficking to lysosomal compartments and in membrane docking/fusion reactions of late endosomes/lysosomes. Required for proper trafficking and targeting of the collagen-modifying enzyme lysyl hydroxylase 3 (LH3) to intracellular collagen. Mediates phagolysosomal fusion in macrophages. Proposed to be involved in endosomal maturation implicating VIPAS39. In epithelial cells, the VPS33B:VIPAS39 complex may play a role in the apical recycling pathway and in the maintenance of the apical-basolateral polarity. Seems to be involved in the sorting of specific cargos from the trans-Golgi network to alpha-granule-destined multivesicular bodies (MVBs) promoting MVBs maturation in megakaryocytes.

Subunit / interactions. Interacts with RAB11A and VIPAS39. Interacts with RAB25. Associates with adapter protein complex 3 (AP-3), clathrin:AP-3 and clathrin:HGS complexes. (Microbial infection) Interacts with M.tuberculosis PtpA.

Subcellular location. Late endosome membrane. Lysosome membrane. Early endosome. Cytoplasmic vesicle. Clathrin-coated vesicle. Recycling endosome.

Tissue specificity. Ubiquitous; highly expressed in testis and low expression in the lung.

Post-translational modifications. Phosphorylated on tyrosine residues. (Microbial infection) Dephosphorylated by M.tuberculosis PtpA, which induces the reduction of host phagolysosome fusion in M.tuberculosis-infected macrophages.

Disease relevance. Arthrogryposis, renal dysfunction, and cholestasis 1 (ARCS1) [MIM:208085] An autosomal recessive multisystem disorder with characteristics of congenital joint contractures, renal tubular dysfunction, neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase activity, severe failure to thrive, ichthyosis, and a defect in platelet alpha-granule biogenesis. Most patients do not survive past the first year of life. The disease is caused by variants affecting the gene represented in this entry. Keratoderma-ichthyosis-deafness syndrome, autosomal recessive (KDIDAR) [MIM:620009] An autosomal recessive disorder characterized by severe palmoplantar keratoderma, generalized ichthyosis, and sensorineural bilateral hearing loss. Additional variable features include contractures, mild bleeding diathesis, and psychomotor retardation. The disease is caused by variants affecting the gene represented in this entry. Cholestasis, progressive familial intrahepatic, 12 (PFIC12) [MIM:620010] A form of progressive cholestasis, a disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease. PFIC12 is an autosomal recessive form characterized by neonatal-onset jaundice and conjugated hyperbilirubinemia, associated with intense pruritus. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the STXBP/unc-18/SEC1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H267-1	1	yes
Q9H267-2	2

RefSeq proteins (3): NP_001276077, NP_001276078, NP_061138* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001619	Sec1-like	Family
IPR027482	Sec1-like_dom2	Homologous_superfamily
IPR036045	Sec1-like_sf	Homologous_superfamily
IPR043127	Sec-1-like_dom3a	Homologous_superfamily
IPR043154	Sec-1-like_dom1	Homologous_superfamily
IPR043155	VPS33_dom3b	Homologous_superfamily

Pfam: PF00995

UniProt features (23 total): mutagenesis site 10, sequence variant 7, sequence conflict 2, initiator methionine 1, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H267-F1	91.82	0.85

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 2

Mutagenesis-validated functional residues (10):

Position	Phenotype
133	reduces phosphorylation activity, but does not impair phagolysosomal fusion in m.tuberculosis-infected macrophages; when
232–234	disrupts interaction with vipas39.
234	no effect on interaction with vipas39; no effect on interaction with stx7 and association with the hops complex; impairs
235–237	disrupts interaction with vipas39.
249	disrupts interaction with vipas39; no effect on interaction with stx7; impairs localization to vipas39-containing endoso
251–253	disrupts interaction with vipas39.
252	no effect on interaction with vipas39 and stx7; impairs localization to vipas39-containing endosomal compartment.
382	reduces phosphorylation activity, but does not impair phagolysosomal fusion in m.tuberculosis-infected macrophages; when
511	reduces phosphorylation activity, but does not impair phagolysosomal fusion in m.tuberculosis-infected macrophages; when
517	reduces phosphorylation activity, but does not impair phagolysosomal fusion in m.tuberculosis-infected macrophages; when

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9636383	Prevention of phagosomal-lysosomal fusion
R-HSA-9754560	SARS-CoV-2 modulates autophagy

MSigDB gene sets: 360 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_PIGMENT_GRANULE_LOCALIZATION, GOBP_LYSOSOMAL_TRANSPORT, GOBP_ENDOSOME_ORGANIZATION, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_VACUOLE_ORGANIZATION, GOBP_VESICLE_LOCALIZATION, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_VESICLE_ORGANIZATION, GOBP_PLATELET_ACTIVATION

GO Biological Process (15): intracellular protein transport (GO:0006886), endosome organization (GO:0007032), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192), peptidyl-lysine hydroxylation (GO:0017185), collagen fibril organization (GO:0030199), melanosome localization (GO:0032400), lysosome localization (GO:0032418), collagen metabolic process (GO:0032963), megakaryocyte development (GO:0035855), skin morphogenesis (GO:0043589), membrane fusion (GO:0061025), platelet alpha granule organization (GO:0070889), regulation of platelet aggregation (GO:0090330), phagosome-lysosome fusion (GO:0090385)

GO Molecular Function (2): protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (20): cytoplasm (GO:0005737), lysosome (GO:0005764), lysosomal membrane (GO:0005765), endosome (GO:0005768), late endosome (GO:0005770), Golgi apparatus (GO:0005794), cytosol (GO:0005829), endosome membrane (GO:0010008), clathrin-coated vesicle (GO:0030136), HOPS complex (GO:0030897), platelet alpha granule (GO:0031091), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), CORVET complex (GO:0033263), perinuclear region of cytoplasm (GO:0048471), recycling endosome (GO:0055037), vesicle tethering complex (GO:0099023), early endosome (GO:0005769), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Suppression of phagosomal maturation	1
SARS-CoV-2-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endosome	5
cellular anatomical structure	4
cytoplasm	4
intracellular protein localization	2
transport	2
binding	2
endomembrane system	2
vesicle tethering complex	2
endosome membrane	2
protein transport	1
intracellular transport	1
endomembrane system organization	1
vesicle organization	1
establishment of protein localization	1
cellular process	1
protein hydroxylation	1
peptidyl-lysine modification	1
extracellular matrix organization	1
pigment granule localization	1
vacuolar localization	1
metabolic process	1
megakaryocyte differentiation	1
myeloid cell development	1
animal organ morphogenesis	1
skin development	1
membrane organization	1
secretory granule organization	1
regulation of platelet activation	1
regulation of homotypic cell-cell adhesion	1
platelet aggregation	1
phagolysosome assembly	1
vesicle fusion	1
intracellular anatomical structure	1
lytic vacuole	1
lysosome	1
lytic vacuole membrane	1
cytoplasmic vesicle	1
intracellular membrane-bounded organelle	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1

Protein interactions and networks

STRING

2010 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VPS33B	VIPAS39	Q9H9C1	999
VPS33B	RAB11A	P24410	940
VPS33B	CFAP45	Q9UL16	793
VPS33B	STX12	Q86Y82	792
VPS33B	VPS11	Q9H270	759
VPS33B	STX8	Q9UNK0	741
VPS33B	STX7	O15400	740
VPS33B	CEACAM5	P06731	674
VPS33B	VPS16	Q9H269	674
VPS33B	VPS39	Q96JC1	644
VPS33B	NBEAL2	Q6ZNJ1	642
VPS33B	VPS18	Q9P253	623
VPS33B	STXBP2	Q15833	610
VPS33B	VPS8	Q8N3P4	606
VPS33B	TGFBRAP1	Q8WUH2	605

IntAct

105 interactions, top by confidence:

A	B	Type	Score
VPS33B	VIPAS39	psi-mi:“MI:0915”(physical association)	0.980
VIPAS39	VPS33B	psi-mi:“MI:0915”(physical association)	0.980
VIPAS39	VPS33B	psi-mi:“MI:0403”(colocalization)	0.980
CCDC22	CCDC93	psi-mi:“MI:0914”(association)	0.960
TNIP1	VPS33B	psi-mi:“MI:0915”(physical association)	0.810
VPS33B	TNIP1	psi-mi:“MI:0915”(physical association)	0.810

BioGRID (251): VPS33B (Two-hybrid), VIPAS39 (Two-hybrid), VPS33B (Affinity Capture-MS), VIPAS39 (Two-hybrid), VPS33B (Affinity Capture-MS), VPS33B (Affinity Capture-Western), VIPAS39 (Affinity Capture-Western), VPS33B (Proximity Label-MS), VPS33B (Affinity Capture-MS), VPS33B (Affinity Capture-MS), VPS33B (Affinity Capture-Western), VPS33B (Affinity Capture-Western), VPS33B (Affinity Capture-Western), VPS33B (Affinity Capture-Western), VIPAS39 (Affinity Capture-Western)

ESM2 similar proteins: A0MT11, A1Z3X3, E9PZQ0, F1LMY4, O00291, O70422, O75146, O97583, P0CL18, P11716, P16960, P21817, P41214, P52849, P52850, P59016, P60027, Q12980, Q15334, Q1LVW0, Q2HJ18, Q53PC7, Q5E9L7, Q5R812, Q5RA63, Q5U3V9, Q5ZIH2, Q63616, Q6NYU2, Q6Q0N3, Q6WKZ8, Q80YV4, Q8IWV8, Q8R1T1, Q8VIJ8, Q8WUX9, Q91W86, Q920Q4, Q92759, Q92889

Diamond homologs: P59016, Q2HJ18, Q58EN8, Q63615, Q63616, Q94KJ7, Q96AX1, Q9D2N9, Q9H267, Q9P7V6, Q9Y1I2

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
VPS33B	“form complex”	“CHEVI complex”	binding
PTPRA	“down-regulates activity”	VPS33B	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 62 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Collagen biosynthesis and modifying enzymes	7	29.1×	1e-06
ECM proteoglycans	5	18.3×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
collagen fibril organization	8	34.6×	3e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

605 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	26
Uncertain significance	251
Likely benign	170
Benign	64

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1323756	NM_018668.5(VPS33B):c.277C>T (p.Arg93Ter)	Pathogenic
1328111	GRCh37/hg19 15q25.3-26.2(chr15:88465861-94411846)x1	Pathogenic
1526045	NM_018668.5(VPS33B):c.67C>T (p.Arg23Ter)	Pathogenic
1526115	NM_018668.5(VPS33B):c.1509dup (p.Lys504fs)	Pathogenic
1686295	NM_018668.5(VPS33B):c.1519C>T (p.Arg507Ter)	Pathogenic
1686296	NM_018668.5(VPS33B):c.84T>A (p.Tyr28Ter)	Pathogenic
2201	NM_018668.5(VPS33B):c.1594C>T (p.Arg532Ter)	Pathogenic
2202	NM_018668.5(VPS33B):c.1312C>T (p.Arg438Ter)	Pathogenic
2203	NM_018668.5(VPS33B):c.89T>C (p.Leu30Pro)	Pathogenic
2204	NM_018668.5(VPS33B):c.700+1G>A	Pathogenic
2419079	NM_018668.5(VPS33B):c.778+2T>G	Pathogenic
286653	NM_018668.5(VPS33B):c.1616del (p.Glu539fs)	Pathogenic
317430	NM_018668.5(VPS33B):c.403+2T>A	Pathogenic
3578187	NM_018668.5(VPS33B):c.1235_1236delinsG (p.Pro412fs)	Pathogenic
3721344	NM_018668.5(VPS33B):c.84T>G (p.Tyr28Ter)	Pathogenic
3764590	NM_018668.5(VPS33B):c.290-2_291del	Pathogenic
419058	NM_018668.5(VPS33B):c.242del (p.Leu81fs)	Pathogenic
4277497	NM_018668.5(VPS33B):c.1751T>C (p.Leu584Pro)	Pathogenic
4277498	NM_018668.5(VPS33B):c.1567C>T (p.Arg523Ter)	Pathogenic
4293655	NM_018668.5(VPS33B):c.1344del (p.Asp450fs)	Pathogenic
4537378	NM_018668.5(VPS33B):c.1106-35_1106-7delinsGGT	Pathogenic
500321	NM_018668.5(VPS33B):c.1479+1G>A	Pathogenic
500825	NM_018668.5(VPS33B):c.1246C>T (p.Arg416Ter)	Pathogenic
521757	NM_018668.5(VPS33B):c.832dup (p.Leu278fs)	Pathogenic
523950	NM_018668.5(VPS33B):c.350del (p.Pro117fs)	Pathogenic
587506	NM_018668.5(VPS33B):c.151C>T (p.Arg51Ter)	Pathogenic
595362	NM_018668.5(VPS33B):c.940-2A>G	Pathogenic
694284	NM_018668.5(VPS33B):c.1726T>C (p.Cys576Arg)	Pathogenic
88857	NM_018668.5(VPS33B):c.240-577_290-156del	Pathogenic
88859	NM_018668.5(VPS33B):c.1261_1262del (p.Gln421fs)	Pathogenic

SpliceAI

3012 predictions. Top by Δscore:

Variant	Effect	Δscore
15:91000487:CA:C	donor_loss	1.0000
15:91000488:A:AC	donor_gain	1.0000
15:91000488:A:C	donor_loss	1.0000
15:91000489:C:CC	donor_gain	1.0000
15:91000489:C:CT	donor_loss	1.0000
15:91000489:CCTG:C	donor_gain	1.0000
15:91000587:GGGAT:G	acceptor_gain	1.0000
15:91000588:GGAT:G	acceptor_gain	1.0000
15:91000589:GAT:G	acceptor_gain	1.0000
15:91000590:AT:A	acceptor_gain	1.0000
15:91000590:ATC:A	acceptor_loss	1.0000
15:91000591:TCTGT:T	acceptor_loss	1.0000
15:91000592:C:CA	acceptor_loss	1.0000
15:91000592:C:CC	acceptor_gain	1.0000
15:91000594:G:C	acceptor_gain	1.0000
15:91002045:CTTA:C	donor_loss	1.0000
15:91002046:TTA:T	donor_loss	1.0000
15:91002047:TA:T	donor_loss	1.0000
15:91002049:C:CT	donor_loss	1.0000
15:91002178:TAGCT:T	acceptor_gain	1.0000
15:91002180:GCTC:G	acceptor_loss	1.0000
15:91002181:CT:C	acceptor_gain	1.0000
15:91002182:TC:T	acceptor_loss	1.0000
15:91002183:C:CC	acceptor_gain	1.0000
15:91003080:CTTA:C	donor_loss	1.0000
15:91003084:C:CA	donor_loss	1.0000
15:91003127:CAAAC:C	acceptor_gain	1.0000
15:91003128:AAAC:A	acceptor_gain	1.0000
15:91003132:C:CC	acceptor_gain	1.0000
15:91003132:CTAA:C	acceptor_loss	1.0000

AlphaMissense

4082 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:91005744:A:T	V327E	1.000
15:91007906:G:C	S154R	1.000
15:91007906:G:T	S154R	1.000
15:91007908:T:G	S154R	1.000
15:91017809:A:G	L58P	1.000
15:91017824:G:T	A53D	1.000
15:91017848:A:G	L45P	1.000
15:91022173:A:G	L26P	1.000
15:90999697:C:G	R585P	0.999
15:91000515:G:C	P519R	0.999
15:91002145:A:G	L437P	0.999
15:91003093:A:C	Y422D	0.999
15:91003104:A:G	L418P	0.999
15:91004897:A:G	L402P	0.999
15:91004901:A:G	C401R	0.999
15:91005445:G:T	A347D	0.999
15:91005702:A:G	L341P	0.999
15:91005732:A:G	L331P	0.999
15:91005746:G:C	F326L	0.999
15:91005746:G:T	F326L	0.999
15:91005748:A:G	F326L	0.999
15:91005999:C:G	A305P	0.999
15:91006010:A:G	L301S	0.999
15:91006043:C:G	R290P	0.999
15:91006439:A:T	V262D	0.999
15:91006445:C:T	G260E	0.999
15:91006652:C:A	G260W	0.999
15:91006681:A:G	L250P	0.999
15:91006685:C:G	G249R	0.999
15:91006952:C:A	R233I	0.999

dbSNP variants (sampled 300 via entrez): RS1000089160 (15:91015208 T>C), RS1000224830 (15:91009475 T>A), RS1000257365 (15:91009650 C>T), RS1000291058 (15:91006581 G>A,T), RS1000336067 (15:90998148 C>T), RS1000808364 (15:91024311 C>G,T), RS1000845970 (15:91003800 G>C,T), RS1000862688 (15:91019603 T>C), RS1000910293 (15:91019337 C>G,T), RS1000920719 (15:91018004 G>A), RS1000968869 (15:91012186 GC>G), RS1001021453 (15:91012370 C>T), RS1001126443 (15:91014293 T>C), RS1001458435 (15:91002698 G>A), RS1001494041 (15:91013966 C>T)

Disease associations

OMIM: gene MIM:608552 | disease phenotypes: MIM:208085, MIM:620010, MIM:620009

GenCC curated gene-disease

Disease	Classification	Inheritance
arthrogryposis, renal dysfunction, and cholestasis 1	Definitive	Autosomal recessive
keratoderma-ichthyosis-deafness syndrome, autosomal recessive	Moderate	Autosomal recessive
arthrogryposis-renal dysfunction-cholestasis syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
arthrogryposis, renal dysfunction, and cholestasis 1	Definitive	AR

Mondo (6): arthrogryposis, renal dysfunction, and cholestasis 1 (MONDO:0008822), cholestasis, progressive familial intrahepatic, 12 (MONDO:0031040), keratoderma-ichthyosis-deafness syndrome, autosomal recessive (MONDO:0859278), thrombocytopenia (MONDO:0002049), microcephaly (MONDO:0001149), arthrogryposis-renal dysfunction-cholestasis syndrome (MONDO:0017123)

Orphanet (1): Arthrogryposis-renal dysfunction-cholestasis syndrome (Orphanet:2697)

HPO phenotypes

77 total (30 of 77 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000092	Renal tubular atrophy
HP:0000093	Proteinuria
HP:0000112	Nephropathy
HP:0000121	Nephrocalcinosis
HP:0000124	Renal tubular dysfunction
HP:0000252	Microcephaly
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000821	Hypothyroidism
HP:0000938	Osteopenia
HP:0000952	Jaundice
HP:0000962	Hyperkeratosis
HP:0000973	Cutis laxa
HP:0000989	Pruritus
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001339	Lissencephaly
HP:0001385	Hip dysplasia
HP:0001396	Cholestasis
HP:0001508	Failure to thrive
HP:0001518	Small for gestational age
HP:0001522	Death in infancy
HP:0001531	Failure to thrive in infancy
HP:0001558	Decreased fetal movement

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST006951_7	Feeling hurt	2.000000e-09
GCST009879_3	Coronary artery disease	3.000000e-29
GCST010476_4	Myocardial infarction	2.000000e-25
GCST010477_6	Hypertension	5.000000e-07
GCST010478_7	Chronic kidney disease	8.000000e-08
GCST010836_2	Ischemic stroke	6.000000e-09
GCST90002404_328	Red cell distribution width	6.000000e-16

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009599	feeling emotionally hurt measurement
EFO:0009188	Red cell distribution width

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C535382	Arthrogryposis renal dysfunction cholestasis syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Cadmium Chloride	decreases expression	2
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
decabromobiphenyl ether	decreases expression	1
sodium arsenite	decreases expression, increases abundance	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Carbamazepine	affects expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Phthalic Acids	decreases methylation	1

Clinical trials (associated diseases)

257 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE
NCT02487563	PHASE3	COMPLETED	Prospective Study of Patients With Thrombocytopenia Following HSCT
NCT02578901	PHASE3	COMPLETED	American Trial Using Tranexamic Acid in Thrombocytopenia
NCT03326843	PHASE3	TERMINATED	Avatrombopag for the Treatment of Thrombocytopenia in Adults Scheduled for a Surgical Procedure
NCT03515096	PHASE3	COMPLETED	Eltrombopag vs. rhTPO to Increase Platelet Level After HSCT
NCT05563064	PHASE3	UNKNOWN	Effect of Herbal Formulation on Thrombocytes Count
NCT07442513	PHASE3	RECRUITING	Comparison of Etamsylate Versus Placebo to Prevent Bleeding in HSCT