Progressive familial intrahepatic cholestasis type 3

Summary

Progressive familial intrahepatic cholestasis type 3 (MONDO:0011214) is a disease caused by ABCB4 (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Causal gene: ABCB4 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 167
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive familial intrahepatic cholestasis type 3
Mondo ID	MONDO:0011214
MeSH	C535935
OMIM	602347
Orphanet	79305
DOID	DOID:0070223
ICD-11	1276600959
UMLS	C1865643
MedGen	356333
GARD	0001289
NORD	1416
Is cancer (heuristic)	no

Also known as: ABCB4 progressive familial intrahepatic cholestasis · cholestasis, progressive familial intrahepatic 3 · cholestasis, progressive familial intrahepatic, 3 · cholestasis, progressive familial intrahepatic, type 3 · MDR3 Deficiency · PFIC3 · progressive familial intrahepatic cholestasis caused by mutation in ABCB4 · progressive familial intrahepatic cholestasis with elevated serum gamma-glutamyltransferase

Data availability: 167 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › progressive familial intrahepatic cholestasis › progressive familial intrahepatic cholestasis type 3

Related subtypes (15): progressive familial intrahepatic cholestasis type 1, benign recurrent intrahepatic cholestasis type 1, progressive familial intrahepatic cholestasis type 2, 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, 12, 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

167 retrieved; paginated sample, class counts are floors:

46 conflicting classifications of pathogenicity, 44 uncertain significance, 22 pathogenic, 22 pathogenic/likely pathogenic, 14 likely pathogenic, 10 benign/likely benign, 9 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
501603	NM_003742.4(ABCB11):c.2494C>T (p.Arg832Cys)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13686	NM_000443.4(ABCB4):c.394_400del (p.Tyr132fs)	ABCB4	Pathogenic	criteria provided, single submitter
13687	NM_000443.4(ABCB4):c.2869C>T (p.Arg957Ter)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13688	NM_000443.4(ABCB4):c.1712del (p.Val571fs)	ABCB4	Pathogenic	criteria provided, single submitter
13690	NM_000443.4(ABCB4):c.959C>T (p.Ser320Phe)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13694	NM_000443.4(ABCB4):c.2169dup (p.Leu724fs)	ABCB4	Pathogenic	criteria provided, single submitter
13696	NM_000443.4(ABCB4):c.430C>T (p.Arg144Ter)	ABCB4	Pathogenic	criteria provided, multiple submitters, no conflicts
1685489	NM_000443.4(ABCB4):c.2682+1G>A	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
194708	NM_000443.4(ABCB4):c.2211+1G>A	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
194709	NM_000443.4(ABCB4):c.2177C>T (p.Pro726Leu)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2498173	NM_000443.4(ABCB4):c.2200G>T (p.Glu734Ter)	ABCB4	Pathogenic	criteria provided, multiple submitters, no conflicts
2628376	NM_000443.4(ABCB4):c.1216C>T (p.Arg406Ter)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2687808	NM_000443.4(ABCB4):c.2306_2309del (p.Phe769fs)	ABCB4	Pathogenic	criteria provided, single submitter
2687809	NM_000443.4(ABCB4):c.1436C>T (p.Pro479Leu)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2687810	NM_000443.4(ABCB4):c.3770del (p.Gln1257fs)	ABCB4	Pathogenic	criteria provided, single submitter
2687811	NM_000443.4(ABCB4):c.1733C>T (p.Ala578Val)	ABCB4	Pathogenic	criteria provided, single submitter
2687812	NM_000443.4(ABCB4):c.153G>A (p.Trp51Ter)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2687813	NM_000443.4(ABCB4):c.3412del (p.Val1138fs)	ABCB4	Pathogenic	criteria provided, single submitter
2687815	NM_000443.4(ABCB4):c.1635del (p.Ala546fs)	ABCB4	Pathogenic	criteria provided, single submitter
2687818	NM_000443.4(ABCB4):c.88_91del (p.Lys30fs)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2687820	NM_000443.4(ABCB4):c.2864G>T (p.Cys955Phe)	ABCB4	Pathogenic	criteria provided, single submitter
2687821	NM_000443.4(ABCB4):c.784del (p.Ala262fs)	ABCB4	Pathogenic	criteria provided, single submitter
2687836	NM_000443.4(ABCB4):c.1906C>T (p.Gln636Ter)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2735041	NM_000443.4(ABCB4):c.1768C>T (p.Arg590Ter)	ABCB4	Pathogenic	criteria provided, multiple submitters, no conflicts
283134	NM_000443.4(ABCB4):c.2833C>T (p.Gln945Ter)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3242002	NM_000443.4(ABCB4):c.202G>A (p.Gly68Arg)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3344889	NM_000443.4(ABCB4):c.287-1G>A	ABCB4	Pathogenic	criteria provided, single submitter
3594921	NM_000443.4(ABCB4):c.3139_3141delinsCC (p.Ala1047fs)	ABCB4	Pathogenic	criteria provided, multiple submitters, no conflicts
372802	NM_000443.4(ABCB4):c.526C>T (p.Arg176Trp)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
497633	NM_000443.4(ABCB4):c.3081+1G>C	ABCB4	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 6 · 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
ABCB4	Strong	Autosomal recessive	progressive familial intrahepatic cholestasis type 3	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCB4	Orphanet:69663	Low phospholipid-associated cholelithiasis
ABCB4	Orphanet:69665	Intrahepatic cholestasis of pregnancy
ABCB4	Orphanet:79305	Progressive familial intrahepatic cholestasis type 3
ABCB11	Orphanet:69665	Intrahepatic cholestasis of pregnancy
ABCB11	Orphanet:79304	Progressive familial intrahepatic cholestasis type 2
ABCB11	Orphanet:99961	Benign recurrent intrahepatic cholestasis type 2

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCB4	HGNC:45	ENSG00000005471	P21439	Phosphatidylcholine translocator ABCB4	gencc,clinvar
ABCB11	HGNC:42	ENSG00000073734	O95342	Bile salt export pump	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABCB4	Phosphatidylcholine translocator ABCB4	Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion.
ABCB11	Bile salt export pump	Catalyzes the transport of the major hydrophobic bile salts, such as taurine and glycine-conjugated cholic acid across the canalicular membrane of hepatocytes in an ATP-dependent manner, therefore participates in hepatic bile acid homeosta…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Transporter	2	77.8×	2e-04

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCB4	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom
ABCB11	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
oocyte	1
secondary oocyte	1
liver	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCB4	188	broad	marker	right lobe of liver, secondary oocyte, oocyte
ABCB11	125	tissue_specific	marker	right lobe of liver, liver, thymus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCB11	2,407
ABCB4	2,333

Intra-cohort edges

A	B	Sources
ABCB11	ABCB4	biogrid_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCB11	O95342	8
ABCB4	P21439	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 2 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
ABC transporter disorders	2	439.2×	8e-05	ABCB4, ABCB11
Disorders of transmembrane transporters	2	139.3×	4e-04	ABCB4, ABCB11
Defective ABCB11 causes PFIC2 and BRIC2	1	5710.0×	7e-04	ABCB11
Defective ABCB4 causes PFIC3, ICP3 and GBD1	1	5710.0×	7e-04	ABCB4
Metabolism of lipids	2	31.6×	0.003	ABCB4, ABCB11
Recycling of bile acids and salts	1	300.5×	0.009	ABCB11
Bile acid and bile salt metabolism	1	248.3×	0.009	ABCB11
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	228.4×	0.009	ABCB11
Synthesis of bile acids and bile salts	1	203.9×	0.009	ABCB11
Disease	2	13.1×	0.009	ABCB4, ABCB11
Metabolism	2	11.6×	0.011	ABCB4, ABCB11
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.018	ABCB4
Metabolism of steroids	1	68.8×	0.018	ABCB11
ABC-family protein mediated transport	1	60.7×	0.019	ABCB4
PPARA activates gene expression	1	47.2×	0.022	ABCB4
Transport of small molecules	1	12.6×	0.078	ABCB4

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lipid homeostasis	2	337.0×	2e-04	ABCB4, ABCB11
transmembrane transport	2	168.5×	4e-04	ABCB4, ABCB11
canalicular bile acid transport	1	8426.0×	7e-04	ABCB11
positive regulation of bile acid secretion	1	8426.0×	7e-04	ABCB11
response to fenofibrate	1	4213.0×	0.001	ABCB4
xenobiotic export from cell	1	2808.7×	0.001	ABCB11
obsolete regulation of bile acid metabolic process	1	2808.7×	0.001	ABCB11
positive regulation of phospholipid translocation	1	2106.5×	0.001	ABCB4
cellular response to bile acid	1	2106.5×	0.001	ABCB4
bile acid secretion	1	1685.2×	0.001	ABCB4
regulation of fatty acid beta-oxidation	1	1404.3×	0.002	ABCB11
positive regulation of cholesterol transport	1	1203.7×	0.002	ABCB4
positive regulation of phospholipid transport	1	1203.7×	0.002	ABCB4
bile acid metabolic process	1	495.6×	0.003	ABCB11
phospholipid homeostasis	1	495.6×	0.003	ABCB11
xenobiotic transmembrane transport	1	468.1×	0.003	ABCB11
bile acid and bile salt transport	1	324.1×	0.004	ABCB11
bile acid biosynthetic process	1	312.1×	0.004	ABCB11
phospholipid translocation	1	312.1×	0.004	ABCB4
fatty acid metabolic process	1	96.8×	0.012	ABCB11
cholesterol homeostasis	1	78.0×	0.015	ABCB11
xenobiotic metabolic process	1	74.6×	0.015	ABCB11
lipid metabolic process	1	45.8×	0.023	ABCB4
protein ubiquitination	1	20.7×	0.048	ABCB11

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ABCB11	TELMISARTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCB11	327	4
ABCB4	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TELMISARTAN	4	ABCB11
BEXAROTENE	4	ABCB11
PROGESTERONE	4	ABCB11
CLOTRIMAZOLE	4	ABCB11
LATANOPROST	4	ABCB11
SIMVASTATIN	4	ABCB11
METHYSERGIDE	4	ABCB11
VALSARTAN	4	ABCB11
BROMFENAC	4	ABCB11
CLOPIDOGREL BISULFATE	4	ABCB11
DIBUCAINE	4	ABCB11
VALRUBICIN	4	ABCB11
RIMONABANT	4	ABCB11
ARIPIPRAZOLE	4	ABCB11
DICYCLOMINE	4	ABCB11
ACITRETIN	4	ABCB11
TELITHROMYCIN	4	ABCB11
EZETIMIBE	4	ABCB11
SAQUINAVIR	4	ABCB11
CLOBETASOL PROPIONATE	4	ABCB11
AMPRENAVIR	4	ABCB11
MOMETASONE FUROATE	4	ABCB11
NORETHINDRONE	4	ABCB11
ATAZANAVIR	4	ABCB11
FEBUXOSTAT	4	ABCB11
PONATINIB	4	ABCB11
TETRABENAZINE	4	ABCB11
CELECOXIB	4	ABCB11
VILANTEROL	4	ABCB11
EXEMESTANE	4	ABCB11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ABCB11	85	Binding:37, ADMET:31, Functional:13, Toxicity:4
ABCB4	4	ADMET:3, Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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.

Compound	Max phase	Cohort target (bioactivity)
TELMISARTAN	4	ABCB11
BEXAROTENE	4	ABCB11
PROGESTERONE	4	ABCB11
CLOTRIMAZOLE	4	ABCB11
LATANOPROST	4	ABCB11
SIMVASTATIN	4	ABCB11
METHYSERGIDE	4	ABCB11
VALSARTAN	4	ABCB11
BROMFENAC	4	ABCB11
CLOPIDOGREL BISULFATE	4	ABCB11
DIBUCAINE	4	ABCB11
VALRUBICIN	4	ABCB11
RIMONABANT	4	ABCB11
ARIPIPRAZOLE	4	ABCB11
DICYCLOMINE	4	ABCB11
ACITRETIN	4	ABCB11
TELITHROMYCIN	4	ABCB11
EZETIMIBE	4	ABCB11
SAQUINAVIR	4	ABCB11
CLOBETASOL PROPIONATE	4	ABCB11
AMPRENAVIR	4	ABCB11
MOMETASONE FUROATE	4	ABCB11
NORETHINDRONE	4	ABCB11
ATAZANAVIR	4	ABCB11
FEBUXOSTAT	4	ABCB11
PONATINIB	4	ABCB11
TETRABENAZINE	4	ABCB11
CELECOXIB	4	ABCB11
VILANTEROL	4	ABCB11
EXEMESTANE	4	ABCB11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ABCB11
B	Phased (≥1) drug, not yet approved	1	ABCB4
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01383746	PHASE1/PHASE2	TERMINATED	Second-line Therapy of Unresectable Cholangiocarcinoma by RADIOEMBOLIZATION