Cholestasis, progressive familial intrahepatic, 12

Summary

Cholestasis, progressive familial intrahepatic, 12 (MONDO:0031040) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 110

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cholestasis, progressive familial intrahepatic, 12
Mondo ID	MONDO:0031040
OMIM	620010
UMLS	C5774311
MedGen	1824084
GARD	0025680
Is cancer (heuristic)	no

Also known as: cholestasis, isolated low-ggt · cholestasis, progressive familial intrahepatic, 12 · PFIC12

Data availability: 110 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › progressive familial intrahepatic cholestasis › cholestasis, progressive familial intrahepatic, 12

Related subtypes (15): progressive familial intrahepatic cholestasis type 1, benign recurrent intrahepatic cholestasis type 1, progressive familial intrahepatic cholestasis type 2, progressive familial intrahepatic cholestasis type 3, hereditary North American Indian childhood cirrhosis, cholestasis, progressive familial intrahepatic, 4, cholestasis, progressive familial intrahepatic, 5, MYO5B-related progressive familial intrahepatic cholestasis, cholestasis, progressive familial intrahepatic, 6, cholestasis, progressive familial intrahepatic, 7, with or without hearing loss, cholestasis, progressive familial intrahepatic, 8, cholestasis, progressive familial intrahepatic, 9, cholestasis, progressive familial intrahepatic, 10, cholestasis, progressive familial intrahepatic, 11, cholestasis, progressive familial intrahepatic, 13

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

110 retrieved; paginated sample, class counts are floors:

81 uncertain significance, 10 likely pathogenic, 9 pathogenic, 6 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323756	NM_018668.5(VPS33B):c.277C>T (p.Arg93Ter)	VPS33B	Pathogenic	criteria provided, multiple submitters, no conflicts
1526115	NM_018668.5(VPS33B):c.1509dup (p.Lys504fs)	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
2202	NM_018668.5(VPS33B):c.1312C>T (p.Arg438Ter)	VPS33B	Pathogenic	criteria provided, multiple submitters, no conflicts
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
419058	NM_018668.5(VPS33B):c.242del (p.Leu81fs)	VPS33B	Pathogenic	criteria provided, multiple submitters, no conflicts
4277498	NM_018668.5(VPS33B):c.1567C>T (p.Arg523Ter)	VPS33B	Pathogenic	criteria provided, multiple submitters, no conflicts
437260	NM_018668.5(VPS33B):c.1498G>T (p.Glu500Ter)	VPS33B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
500160	NM_018668.5(VPS33B):c.239+5G>A	VPS33B	Pathogenic/Likely 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
694284	NM_018668.5(VPS33B):c.1726T>C (p.Cys576Arg)	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
3578178	NM_018668.5(VPS33B):c.1480-1G>T	VPS33B	Likely pathogenic	criteria provided, single submitter
3578185	NM_018668.5(VPS33B):c.1283del (p.Pro428fs)	VPS33B	Likely pathogenic	criteria provided, single submitter
3578193	NM_018668.5(VPS33B):c.1030+1G>A	VPS33B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3578203	NM_018668.5(VPS33B):c.778+1G>T	VPS33B	Likely pathogenic	criteria provided, single submitter
3578206	NM_018668.5(VPS33B):c.672_673del (p.Glu224fs)	VPS33B	Likely pathogenic	criteria provided, single submitter
3578208	NM_018668.5(VPS33B):c.600del (p.Lys201fs)	VPS33B	Likely pathogenic	criteria provided, single submitter
3578220	NM_018668.5(VPS33B):c.290-1G>A	VPS33B	Likely pathogenic	criteria provided, single submitter
3578224	NM_018668.5(VPS33B):c.177+1G>A	VPS33B	Likely pathogenic	criteria provided, single submitter
3602638	NM_018668.5(VPS33B):c.853-1G>C	VPS33B	Likely pathogenic	criteria provided, single submitter
3780787	NM_018668.5(VPS33B):c.1236del (p.Lys413fs)	VPS33B	Likely pathogenic	criteria provided, single submitter
1028605	NM_018668.5(VPS33B):c.1780A>G (p.Arg594Gly)	VPS33B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2999951	NM_018668.5(VPS33B):c.1384C>T (p.Leu462=)	VPS33B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317421	NM_018668.5(VPS33B):c.1274G>A (p.Ser425Asn)	VPS33B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
594774	NM_018668.5(VPS33B):c.403G>A (p.Asp135Asn)	VPS33B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028606	NM_018668.5(VPS33B):c.44T>C (p.Phe15Ser)	VPS33B	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VPS33B	Orphanet:2697	Arthrogryposis-renal dysfunction-cholestasis syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VPS33B	HGNC:12712	ENSG00000184056	Q9H267	Vacuolar protein sorting-associated protein 33B	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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VPS33B	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
middle temporal gyrus	1
pancreatic ductal cell	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VPS33B	2,366

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VPS33B	Q9H267	91.82

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 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	1268.9×	1e-03	VPS33B
SARS-CoV-2 modulates autophagy	1	1038.2×	1e-03	VPS33B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
platelet alpha granule organization	1	8426.0×	0.001	VPS33B
peptidyl-lysine hydroxylation	1	4213.0×	0.001	VPS33B
melanosome localization	1	3370.4×	0.001	VPS33B
regulation of platelet aggregation	1	2407.4×	0.002	VPS33B
skin morphogenesis	1	1404.3×	0.002	VPS33B
phagosome-lysosome fusion	1	1296.3×	0.002	VPS33B
collagen metabolic process	1	1053.2×	0.002	VPS33B
megakaryocyte development	1	702.2×	0.003	VPS33B
membrane fusion	1	624.1×	0.003	VPS33B
lysosome localization	1	526.6×	0.003	VPS33B
endosome organization	1	374.5×	0.004	VPS33B
collagen fibril organization	1	224.7×	0.006	VPS33B
vesicle-mediated transport	1	96.3×	0.012	VPS33B
intracellular protein transport	1	64.8×	0.017	VPS33B
protein transport	1	43.9×	0.023	VPS33B

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	VPS33B

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.