Cholestasis, progressive familial intrahepatic, 4
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Also known as cholestasis, progressive familial intrahepatic 4cholestasis, progressive familial intrahepatic, type 4PFIC4progressive familial intrahepatic cholestasis 4progressive familial intrahepatic cholestasis caused by mutation in TJP2progressive familial intrahepatic cholestasis type 4TJP2 deficitTJP2 progressive familial intrahepatic cholestasis
Summary
Cholestasis, progressive familial intrahepatic, 4 (MONDO:0014381) is a disease caused by TJP2 (GenCC Strong), with 2 cohort genes.
At a glance
- Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
- Causal gene: TJP2 (GenCC Strong)
- Cohort genes: 2
- ClinVar variants: 84
Clinical features
Epidemiology
Prevalence records
2 prevalence record(s), Orphanet:
| Type | Class | Value | Geography | Validation |
|---|---|---|---|---|
| Cases/families | 14 | Worldwide | Validated | |
| Point prevalence | <1 / 1 000 000 | Worldwide | Validated |
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | cholestasis, progressive familial intrahepatic, 4 |
| Mondo ID | MONDO:0014381 |
| OMIM | 615878 |
| Orphanet | 480483 |
| DOID | DOID:0070224 |
| UMLS | C2931067 |
| MedGen | 418976 |
| GARD | 0009803 |
| Is cancer (heuristic) | no |
Also known as: cholestasis, progressive familial intrahepatic 4 · cholestasis, progressive familial intrahepatic, 4 · cholestasis, progressive familial intrahepatic, type 4 · PFIC4 · progressive familial intrahepatic cholestasis 4 · progressive familial intrahepatic cholestasis caused by mutation in TJP2 · progressive familial intrahepatic cholestasis type 4 · TJP2 deficit · TJP2 progressive familial intrahepatic cholestasis
Data availability: 84 ClinVar variants · 3 GenCC gene-disease records.
Disease family
Classification path: disease › human disease › disease by body system or component › syndromic disease › progressive familial intrahepatic cholestasis › cholestasis, progressive familial intrahepatic, 4
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, 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
84 retrieved; paginated sample, class counts are floors:
27 pathogenic, 15 uncertain significance, 15 likely pathogenic, 12 conflicting classifications of pathogenicity, 7 benign, 6 pathogenic/likely pathogenic, 1 likely benign, 1 benign/likely benign
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 288555 | NM_003742.4(ABCB11):c.1445A>G (p.Asp482Gly) | ABCB11 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1030844 | NM_004817.4(TJP2):c.2524C>T (p.Gln842Ter) | TJP2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1199419 | NM_004817.4(TJP2):c.1157del (p.Gln386fs) | TJP2 | Pathogenic | no assertion criteria provided |
| 1285612 | NM_004817.4(TJP2):c.2645_2646dup (p.Val883fs) | TJP2 | Pathogenic | no assertion criteria provided |
| 1323690 | NM_004817.4(TJP2):c.3325G>T (p.Glu1109Ter) | TJP2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 139628 | NM_004817.4(TJP2):c.885del (p.Ser296fs) | TJP2 | Pathogenic | no assertion criteria provided |
| 139629 | NM_004817.4(TJP2):c.1361del (p.Ala454fs) | TJP2 | Pathogenic | criteria provided, single submitter |
| 139630 | NM_004817.4(TJP2):c.1992-2A>G | TJP2 | Pathogenic | criteria provided, single submitter |
| 1705691 | NM_004817.4(TJP2):c.2071C>T (p.Gln691Ter) | TJP2 | Pathogenic | criteria provided, single submitter |
| 1806010 | NM_004817.4(TJP2):c.2667+3A>G | TJP2 | Pathogenic | criteria provided, single submitter |
| 1965615 | NM_004817.4(TJP2):c.619C>T (p.Gln207Ter) | TJP2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 217498 | NC_000009.12:g.69254209_69254374del | TJP2 | Pathogenic | criteria provided, single submitter |
| 219195 | NM_004817.4(TJP2):c.2668-1G>T | TJP2 | Pathogenic | no assertion criteria provided |
| 219196 | NM_004817.4(TJP2):c.2438dup (p.Asn814fs) | TJP2 | Pathogenic | no assertion criteria provided |
| 219197 | NM_004817.4(TJP2):c.817del (p.Ala273fs) | TJP2 | Pathogenic | criteria provided, single submitter |
| 2687826 | NM_004817.4(TJP2):c.1765C>T (p.Gln589Ter) | TJP2 | Pathogenic | criteria provided, single submitter |
| 280808 | NM_004817.4(TJP2):c.570_574dup (p.Ser192fs) | TJP2 | Pathogenic | criteria provided, single submitter |
| 2907 | NM_004817.4(TJP2):c.143T>C (p.Val48Ala) | TJP2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 374295 | NM_004817.4(TJP2):c.1243del (p.Ser415fs) | TJP2 | Pathogenic | no assertion criteria provided |
| 397506 | NC_000009.11:g.(71833276_71835802)_(71855064_71861605)dup | TJP2 | Pathogenic | criteria provided, single submitter |
| 438788 | NM_004817.4(TJP2):c.813_814del (p.Ala273fs) | TJP2 | Pathogenic | no assertion criteria provided |
| 499233 | NM_004817.4(TJP2):c.782del (p.Tyr261fs) | TJP2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 632045 | NM_004817.4(TJP2):c.1894C>T (p.Arg632Ter) | TJP2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 805837 | NM_004817.4(TJP2):c.1672-1G>A | TJP2 | Pathogenic | criteria provided, single submitter |
| 805838 | NM_004817.4(TJP2):c.2209G>A (p.Gly737Ser) | TJP2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 805839 | NM_004817.4(TJP2):c.2908C>T (p.Arg970Ter) | TJP2 | Pathogenic | criteria provided, single submitter |
| 805840 | NM_004817.4(TJP2):c.1292C>G (p.Ser431Ter) | TJP2 | Pathogenic | criteria provided, single submitter |
| 805842 | NM_004817.4(TJP2):c.115-1G>A | TJP2 | Pathogenic | criteria provided, single submitter |
| 805843 | NM_004817.4(TJP2):c.2173C>T (p.Arg725Ter) | TJP2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 805844 | NM_004817.4(TJP2):c.1234C>T (p.Arg412Ter) | TJP2 | 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 |
|---|---|---|---|---|
| TJP2 | Strong | Autosomal recessive | cholestasis, progressive familial intrahepatic, 4 | 9 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| TJP2 | Orphanet:238475 | Familial hypercholanemia |
| TJP2 | Orphanet:480483 | Progressive familial intrahepatic cholestasis type 4 |
| TJP2 | Orphanet:90635 | Rare autosomal dominant non-syndromic sensorineural deafness type DFNA |
| 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 |
|---|---|---|---|---|---|
| TJP2 | HGNC:11828 | ENSG00000119139 | Q9UDY2 | Tight junction protein 2 | 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) |
|---|---|---|
| TJP2 | Tight junction protein 2 | Plays a role in tight junctions and adherens junctions. |
| 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: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5
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 | 1 | 38.9× | 0.051 |
| Scaffold/PPI | 1 | 8.6× | 0.112 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| TJP2 | Scaffold/PPI | no | SH3_domain, PDZ, ZO | |
| 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 |
|---|---|
| corpus callosum | 1 |
| descending thoracic aorta | 1 |
| thoracic aorta | 1 |
| liver | 1 |
| right lobe of liver | 1 |
| thymus | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| TJP2 | 134 | ubiquitous | marker | corpus callosum, descending thoracic aorta, thoracic aorta |
| ABCB11 | 125 | tissue_specific | marker | right lobe of liver, liver, thymus |
Protein interactions among cohort
Intra-cohort edges: 0.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| TJP2 | 2,916 |
| ABCB11 | 2,407 |
Structural data
PDB: 2 · AlphaFold-only: 0 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| ABCB11 | O95342 | 8 |
| TJP2 | Q9UDY2 | 2 |
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 |
|---|---|---|---|---|
| Defective ABCB11 causes PFIC2 and BRIC2 | 1 | 5710.0× | 0.003 | ABCB11 |
| Apoptotic cleavage of cell adhesion proteins | 1 | 519.1× | 0.010 | TJP2 |
| Recycling of bile acids and salts | 1 | 300.5× | 0.010 | ABCB11 |
| Signaling by Hippo | 1 | 271.9× | 0.010 | TJP2 |
| Bile acid and bile salt metabolism | 1 | 248.3× | 0.010 | ABCB11 |
| Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol | 1 | 228.4× | 0.010 | ABCB11 |
| ABC transporter disorders | 1 | 219.6× | 0.010 | ABCB11 |
| Synthesis of bile acids and bile salts | 1 | 203.9× | 0.010 | ABCB11 |
| RHOB GTPase cycle | 1 | 77.2× | 0.019 | TJP2 |
| RHOC GTPase cycle | 1 | 73.2× | 0.019 | TJP2 |
| Disorders of transmembrane transporters | 1 | 69.6× | 0.019 | ABCB11 |
| Metabolism of steroids | 1 | 68.8× | 0.019 | ABCB11 |
| RHOA GTPase cycle | 1 | 37.3× | 0.033 | TJP2 |
| Metabolism of lipids | 1 | 15.8× | 0.071 | ABCB11 |
| Disease | 1 | 6.5× | 0.157 | ABCB11 |
| Metabolism | 1 | 5.8× | 0.165 | ABCB11 |
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 |
|---|---|---|---|---|
| canalicular bile acid transport | 1 | 8426.0× | 0.001 | ABCB11 |
| positive regulation of bile acid secretion | 1 | 8426.0× | 0.001 | ABCB11 |
| xenobiotic export from cell | 1 | 2808.7× | 0.002 | ABCB11 |
| obsolete regulation of bile acid metabolic process | 1 | 2808.7× | 0.002 | ABCB11 |
| positive regulation of blood-brain barrier permeability | 1 | 1685.2× | 0.003 | TJP2 |
| regulation of fatty acid beta-oxidation | 1 | 1404.3× | 0.003 | ABCB11 |
| regulation of membrane permeability | 1 | 1203.7× | 0.003 | TJP2 |
| protein localization to cell-cell junction | 1 | 936.2× | 0.003 | TJP2 |
| homotypic cell-cell adhesion | 1 | 842.6× | 0.003 | TJP2 |
| establishment of endothelial intestinal barrier | 1 | 702.2× | 0.004 | TJP2 |
| intestinal absorption | 1 | 601.9× | 0.004 | TJP2 |
| bile acid metabolic process | 1 | 495.6× | 0.004 | ABCB11 |
| phospholipid homeostasis | 1 | 495.6× | 0.004 | ABCB11 |
| xenobiotic transmembrane transport | 1 | 468.1× | 0.004 | ABCB11 |
| bile acid and bile salt transport | 1 | 324.1× | 0.005 | ABCB11 |
| bile acid biosynthetic process | 1 | 312.1× | 0.005 | ABCB11 |
| cell-cell junction organization | 1 | 312.1× | 0.005 | TJP2 |
| maintenance of blood-brain barrier | 1 | 240.7× | 0.006 | TJP2 |
| lipid homeostasis | 1 | 168.5× | 0.008 | ABCB11 |
| fatty acid metabolic process | 1 | 96.8× | 0.013 | ABCB11 |
| transmembrane transport | 1 | 84.3× | 0.014 | ABCB11 |
| cholesterol homeostasis | 1 | 78.0× | 0.015 | ABCB11 |
| xenobiotic metabolic process | 1 | 74.6× | 0.015 | ABCB11 |
| cell-cell adhesion | 1 | 50.8× | 0.020 | TJP2 |
| protein ubiquitination | 1 | 20.7× | 0.048 | ABCB11 |
Therapeutics
Drug target analysis
Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1
Druggability breadth: 1 of 2 evidence-associated genes (50%) 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 |
| TJP2 | 0 | 0 |
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 |
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 | 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 | TJP2 |
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) |
|---|---|---|
| TJP2 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.