Arthrogryposis, renal dysfunction, and cholestasis 1

Summary

Arthrogryposis, renal dysfunction, and cholestasis 1 (MONDO:0008822) is a disease caused by VPS33B (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: VPS33B (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 190

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arthrogryposis, renal dysfunction, and cholestasis 1
Mondo ID	MONDO:0008822
OMIM	208085
DOID	DOID:0111353
UMLS	C1859722
MedGen	347219
GARD	0015139
Is cancer (heuristic)	no

Also known as: ARCS1 · arthrogryposis, renal dysfunction, and cholestasis 1 · arthrogryposis, renal dysfunction, and cholestasis type 1 · arthrogryposis-renal dysfunction-cholestasis syndrome caused by mutation in VPS33B · VPS33B arthrogryposis-renal dysfunction-cholestasis syndrome

Data availability: 190 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › arthrogryposis-renal dysfunction-cholestasis syndrome › arthrogryposis, renal dysfunction, and cholestasis 1

Related subtypes (1): arthrogryposis, renal dysfunction, and cholestasis 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

190 retrieved; paginated sample, class counts are floors:

109 uncertain significance, 23 pathogenic, 18 likely pathogenic, 14 conflicting classifications of pathogenicity, 10 benign, 8 benign/likely benign, 6 pathogenic/likely pathogenic, 1 association, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
427838	NM_018668.4(VPS33B):c.[1030+1G>T];[319C>T]		Pathogenic	criteria provided, single submitter
1332759	NM_000138.5(FBN1):c.3589+1G>A	FBN1	Pathogenic	criteria provided, single submitter
635326	NM_001193315.2(VIPAS39):c.20del (p.Asp7fs)	VIPAS39	Pathogenic	criteria provided, single submitter
635327	NM_001193315.2(VIPAS39):c.1179+1G>A	VIPAS39	Pathogenic	criteria provided, single submitter
1323756	NM_018668.5(VPS33B):c.277C>T (p.Arg93Ter)	VPS33B	Pathogenic	criteria provided, multiple submitters, no conflicts
1526045	NM_018668.5(VPS33B):c.67C>T (p.Arg23Ter)	VPS33B	Pathogenic	criteria provided, single submitter
1526115	NM_018668.5(VPS33B):c.1509dup (p.Lys504fs)	VPS33B	Pathogenic	criteria provided, multiple submitters, no conflicts
1686295	NM_018668.5(VPS33B):c.1519C>T (p.Arg507Ter)	VPS33B	Pathogenic	criteria provided, multiple submitters, no conflicts
1686296	NM_018668.5(VPS33B):c.84T>A (p.Tyr28Ter)	VPS33B	Pathogenic	criteria provided, multiple submitters, no conflicts
1701813	NM_018668.5(VPS33B):c.240-1G>C	VPS33B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2201	NM_018668.5(VPS33B):c.1594C>T (p.Arg532Ter)	VPS33B	Pathogenic	criteria provided, single submitter
2202	NM_018668.5(VPS33B):c.1312C>T (p.Arg438Ter)	VPS33B	Pathogenic	criteria provided, multiple submitters, no conflicts
2203	NM_018668.5(VPS33B):c.89T>C (p.Leu30Pro)	VPS33B	Pathogenic	no assertion criteria provided
2204	NM_018668.5(VPS33B):c.700+1G>A	VPS33B	Pathogenic	no assertion criteria provided
3029060	NM_018668.5(VPS33B):c.1623_1641del (p.Arg542fs)	VPS33B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
317430	NM_018668.5(VPS33B):c.403+2T>A	VPS33B	Pathogenic	criteria provided, multiple submitters, no conflicts
3578187	NM_018668.5(VPS33B):c.1235_1236delinsG (p.Pro412fs)	VPS33B	Pathogenic	criteria provided, multiple submitters, no conflicts
375326	NM_018668.5(VPS33B):c.319C>T (p.Arg107Ter)	VPS33B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3764590	NM_018668.5(VPS33B):c.290-2_291del	VPS33B	Pathogenic	criteria provided, single submitter
4277497	NM_018668.5(VPS33B):c.1751T>C (p.Leu584Pro)	VPS33B	Pathogenic	criteria provided, single submitter
4293655	NM_018668.5(VPS33B):c.1344del (p.Asp450fs)	VPS33B	Pathogenic	criteria provided, single submitter
437260	NM_018668.5(VPS33B):c.1498G>T (p.Glu500Ter)	VPS33B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4537378	NM_018668.5(VPS33B):c.1106-35_1106-7delinsGGT	VPS33B	Pathogenic	criteria provided, single submitter
500160	NM_018668.5(VPS33B):c.239+5G>A	VPS33B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523950	NM_018668.5(VPS33B):c.350del (p.Pro117fs)	VPS33B	Pathogenic	criteria provided, multiple submitters, no conflicts
587506	NM_018668.5(VPS33B):c.151C>T (p.Arg51Ter)	VPS33B	Pathogenic	criteria provided, multiple submitters, no conflicts
88857	NM_018668.5(VPS33B):c.240-577_290-156del	VPS33B	Pathogenic	no assertion criteria provided
88858	NM_018668.5(VPS33B):c.1225+5G>C	VPS33B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88859	NM_018668.5(VPS33B):c.1261_1262del (p.Gln421fs)	VPS33B	Pathogenic	no assertion criteria provided
3778765	NM_018451.5(CPAP):c.3765_3768dup (p.Pro1257fs)	RNF17	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
VPS33B	Definitive	Autosomal recessive	arthrogryposis, renal dysfunction, and cholestasis 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VPS33B	Orphanet:2697	Arthrogryposis-renal dysfunction-cholestasis syndrome
VIPAS39	Orphanet:2697	Arthrogryposis-renal dysfunction-cholestasis syndrome
FBN1	Orphanet:1885	Isolated ectopia lentis
FBN1	Orphanet:2084	Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome
FBN1	Orphanet:2462	Shprintzen-Goldberg syndrome
FBN1	Orphanet:2623	Geleophysic dysplasia
FBN1	Orphanet:2833	Stiff skin syndrome
FBN1	Orphanet:284963	Marfan syndrome type 1
FBN1	Orphanet:284979	Neonatal Marfan syndrome
FBN1	Orphanet:300382	Progeroid and marfanoid aspect-lipodystrophy syndrome
FBN1	Orphanet:3449	Weill-Marchesani syndrome
FBN1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
FBN1	Orphanet:969	Acromicric dysplasia

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VPS33B	HGNC:12712	ENSG00000184056	Q9H267	Vacuolar protein sorting-associated protein 33B	gencc,clinvar
RNF17	HGNC:10060	ENSG00000132972	Q9BXT8	RING finger protein 17	clinvar
VIPAS39	HGNC:20347	ENSG00000151445	Q9H9C1	Spermatogenesis-defective protein 39 homolog	clinvar
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VPS33B	Vacuolar protein sorting-associated protein 33B	May play a role in vesicle-mediated protein trafficking to lysosomal compartments and in membrane docking/fusion reactions of late endosomes/lysosomes.
RNF17	RING finger protein 17	Seems to be involved in regulation of transcriptional activity of MYC.
VIPAS39	Spermatogenesis-defective protein 39 homolog	Proposed to be involved in endosomal maturation implicating in part VPS33B.
FBN1	Fibrillin-1	Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	2.1×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VPS33B	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
RNF17	Transcription factor	no		Znf_RING, Tudor, Znf_RING_CS
VIPAS39	Other/Unknown	no		Vps16_C, Vps16_C_sf, Spe-39
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
Brodmann (1909) area 23	1
middle temporal gyrus	1
pancreatic ductal cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1
cortical plate	1
ganglionic eminence	1
decidua	1
skin of hip	1
synovial joint	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VPS33B	277	ubiquitous	yes	pancreatic ductal cell, Brodmann (1909) area 23, middle temporal gyrus
RNF17	142	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right testis
VIPAS39	274	ubiquitous	marker	cortical plate, ganglionic eminence, primordial germ cell in gonad
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBN1	3,640
VPS33B	2,366
VIPAS39	1,242
RNF17	1,108

Intra-cohort edges

A	B	Sources
VIPAS39	VPS33B	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FBN1	P35555	11
RNF17	Q9BXT8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VPS33B	Q9H267	91.82
VIPAS39	Q9H9C1	78.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 4 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Prevention of phagosomal-lysosomal fusion	1	634.4×	0.009	VPS33B
SARS-CoV-2 modulates autophagy	1	519.1×	0.009	VPS33B
Elastic fibre formation	1	167.9×	0.012	FBN1
TGF-beta receptor signaling activates SMADs	1	163.1×	0.012	FBN1
Molecules associated with elastic fibres	1	154.3×	0.012	FBN1
Integrin cell surface interactions	1	67.2×	0.022	FBN1
Degradation of the extracellular matrix	1	58.9×	0.022	FBN1
Post-translational protein phosphorylation	1	50.1×	0.022	FBN1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.023	FBN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peptidyl-lysine hydroxylation	2	2106.5×	1e-05	VPS33B, VIPAS39
phagosome-lysosome fusion	2	648.1×	6e-05	VPS33B, VIPAS39
collagen metabolic process	2	526.6×	6e-05	VPS33B, VIPAS39
collagen fibril organization	2	112.3×	0.001	VPS33B, VIPAS39
platelet alpha granule organization	1	2106.5×	0.004	VPS33B
post-embryonic eye morphogenesis	1	1404.3×	0.005	FBN1
obsolete sequestering of BMP in extracellular matrix	1	1053.2×	0.005	FBN1
obsolete sequestering of TGFbeta in extracellular matrix	1	1053.2×	0.005	FBN1
melanosome localization	1	842.6×	0.005	VPS33B
negative regulation of osteoclast development	1	842.6×	0.005	FBN1
vacuolar transport	1	702.2×	0.005	VIPAS39
intracellular protein transport	2	32.4×	0.005	VPS33B, VIPAS39
regulation of platelet aggregation	1	601.9×	0.005	VPS33B
embryonic eye morphogenesis	1	383.0×	0.007	FBN1
skin morphogenesis	1	351.1×	0.007	VPS33B
cellular response to insulin-like growth factor stimulus	1	324.1×	0.007	FBN1
megakaryocyte development	1	175.5×	0.013	VPS33B
cell adhesion mediated by integrin	1	168.5×	0.013	FBN1
membrane fusion	1	156.0×	0.013	VPS33B
negative regulation of osteoclast differentiation	1	135.9×	0.013	FBN1
lysosome localization	1	131.7×	0.013	VPS33B
metanephros development	1	127.7×	0.013	FBN1
post-translational protein modification	1	105.3×	0.016	VIPAS39
endosome organization	1	93.6×	0.017	VPS33B
camera-type eye development	1	89.6×	0.017	FBN1
lung alveolus development	1	87.8×	0.017	FBN1
endosome to lysosome transport	1	84.3×	0.017	VIPAS39
cellular response to transforming growth factor beta stimulus	1	69.1×	0.020	FBN1
glucose metabolic process	1	63.8×	0.020	FBN1
spermatid development	1	36.3×	0.035	RNF17

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 0 of 4 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VPS33B	0	0
RNF17	0	0
VIPAS39	0	0
FBN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	VPS33B, RNF17, VIPAS39, FBN1

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
VPS33B	0	—
RNF17	0	—
VIPAS39	0	—
FBN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.