Familial intrahepatic cholestasis

Summary

Familial intrahepatic cholestasis (MONDO:0017290) is a disease with 4 cohort genes.

At a glance

• Cohort genes: 4
• ClinVar variants: 1,499

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial intrahepatic cholestasis
Mondo ID	MONDO:0017290
Orphanet	284385
SNOMED CT	74162007
GARD	0021119
Is cancer (heuristic)	no

Also known as: hereditary intrahepatic cholestasis

Data availability: 1,499 ClinVar variants.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hepatobiliary disorder › liver disorder › familial intrahepatic cholestasis

Related subtypes (31): polycystic echinococcosis, autosomal dominant polycystic liver disease, hepatorenal syndrome, hepatitis, hepatic vascular disorder, hepatic porphyria, hepatopulmonary syndrome, fatty liver disease, cirrhosis of liver, drug-induced liver injury, perinatal jaundice due to hepatocellular damage, Aagenaes syndrome, transient familial neonatal hyperbilirubinemia, hyperbiliverdinemia, transient infantile hypertriglyceridemia and hepatosteatosis, idiopathic copper-associated cirrhosis, bile duct cyst, nodular regenerative hyperplasia of the liver, hepatoportal sclerosis, primitive portal vein thrombosis, glycogen storage disease due to liver phosphorylase kinase deficiency, liver and intrahepatic bile duct neoplasm, alcoholic liver disease, early-onset familial noncirrhotic portal hypertension, liver failure, fibrotic liver disease, intestinal failure–associated liver disease, liver abscess (disease), membranous obstruction of inferior vena cava, liver disease, severe congenital, cystic fibrosis-related liver disease

Subtypes (4): cholestasis, intrahepatic, of pregnancy, 1, cholestasis, intrahepatic, of pregnancy, 3, progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis

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

600 retrieved; paginated sample, class counts are floors:

183 uncertain significance, 133 conflicting classifications of pathogenicity, 68 pathogenic, 68 benign, 66 pathogenic/likely pathogenic, 32 benign/likely benign, 25 likely benign, 24 likely pathogenic, 1 benign; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028652	NM_003742.4(ABCB11):c.2488del (p.Arg830fs)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
1070201	NM_003742.4(ABCB11):c.2319dup (p.Phe774fs)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070887	NM_003742.4(ABCB11):c.1460G>C (p.Arg487Pro)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074827	NM_003742.4(ABCB11):c.2178+1G>C	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
1075698	NM_003742.4(ABCB11):c.3772C>T (p.Gln1258Ter)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076790	NM_003742.4(ABCB11):c.3491del (p.Val1164fs)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
1076791	NM_003742.4(ABCB11):c.3458G>A (p.Arg1153His)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1383688	NM_003742.4(ABCB11):c.1415A>G (p.Tyr472Cys)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1410817	NM_003742.4(ABCB11):c.3703C>T (p.Arg1235Ter)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
1433215	NM_003742.4(ABCB11):c.483C>A (p.Cys161Ter)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
1446289	NM_003742.4(ABCB11):c.1621A>C (p.Ile541Leu)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1446319	NM_003742.4(ABCB11):c.1243C>T (p.Arg415Ter)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
1446335	NM_003742.4(ABCB11):c.499G>A (p.Ala167Thr)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453316	NM_003742.4(ABCB11):c.3904G>T (p.Glu1302Ter)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
1453324	NM_003742.4(ABCB11):c.1941del (p.Gly648fs)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
1458296	NM_003742.4(ABCB11):c.3174del (p.Gln1058fs)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
1458300	NM_003742.4(ABCB11):c.2343+2T>C	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526234	NM_003742.4(ABCB11):c.611+1G>A	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
1687463	NM_003742.4(ABCB11):c.3400C>T (p.Gln1134Ter)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
1879492	NM_003742.4(ABCB11):c.2012-2A>G	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
2203209	NM_003742.4(ABCB11):c.3438del (p.Lys1146_Val1147insTer)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
2504002	NM_003742.4(ABCB11):c.3803G>A (p.Arg1268Gln)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674786	NM_003742.4(ABCB11):c.1685G>A (p.Gly562Asp)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678310	NM_003742.4(ABCB11):c.2542del (p.Asp848fs)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679521	NM_003742.4(ABCB11):c.1081C>T (p.Gln361Ter)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
2679806	NM_003742.4(ABCB11):c.2316T>G (p.Tyr772Ter)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679906	NM_003742.4(ABCB11):c.2178+1G>T	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
2679946	NM_003742.4(ABCB11):c.779G>A (p.Gly260Asp)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680196	NM_003742.4(ABCB11):c.567G>A (p.Trp189Ter)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
2680334	NM_003742.4(ABCB11):c.2815-2A>G	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP8B1	Orphanet:69665	Intrahepatic cholestasis of pregnancy
ATP8B1	Orphanet:79306	Progressive familial intrahepatic cholestasis type 1
ATP8B1	Orphanet:99960	Benign recurrent intrahepatic cholestasis type 1
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
ABCB4	Orphanet:69663	Low phospholipid-associated cholelithiasis
ABCB4	Orphanet:69665	Intrahepatic cholestasis of pregnancy
ABCB4	Orphanet:79305	Progressive familial intrahepatic cholestasis type 3

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATP8B1	HGNC:3706	ENSG00000081923	O43520	Phospholipid-transporting ATPase IC	clinvar
ABCB11	HGNC:42	ENSG00000073734	O95342	Bile salt export pump	clinvar
ABCB4	HGNC:45	ENSG00000005471	P21439	Phosphatidylcholine translocator ABCB4	clinvar
ATP8B1-AS1	HGNC:56042	ENSG00000267040		ATP8B1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP8B1	Phospholipid-transporting ATPase IC	Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of phospholipids, in particular phosphatidylcholines (PC), from the outer to the inner leaflet of the plasma membrane.
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…
ABCB4	Phosphatidylcholine translocator ABCB4	Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · 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	2	38.9×	0.003
Transcription factor	1	2.1×	0.605
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP8B1	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf
ABCB11	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom
ABCB4	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom
ATP8B1-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

4 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
right lobe of liver	2
cardia of stomach	1
nipple	1
renal medulla	1
liver	1
thymus	1
oocyte	1
secondary oocyte	1
buccal mucosa cell	1
pancreatic ductal cell	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP8B1	289	ubiquitous	marker	cardia of stomach, nipple, renal medulla
ABCB11	125	tissue_specific	marker	right lobe of liver, liver, thymus
ABCB4	188	broad	marker	right lobe of liver, secondary oocyte, oocyte
ATP8B1-AS1	199		marker	buccal mucosa cell, primordial germ cell in gonad, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCB11	2,407
ABCB4	2,333
ATP8B1	1,296
ATP8B1-AS1	0

Intra-cohort edges

A	B	Sources
ABCB11	ABCB4	biogrid_interaction
ABCB11	ATP8B1	string_interaction
ABCB4	ATP8B1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP8B1	O43520	13
ABCB11	O95342	8
ABCB4	P21439	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 4 evidence-associated genes (3 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 3 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	292.8×	3e-04	ABCB11, ABCB4
Defective ABCB11 causes PFIC2 and BRIC2	1	3806.7×	0.001	ABCB11
Defective ABCB4 causes PFIC3, ICP3 and GBD1	1	3806.7×	0.001	ABCB4
Disorders of transmembrane transporters	2	92.8×	0.001	ABCB11, ABCB4
Metabolism of lipids	2	21.0×	0.011	ABCB11, ABCB4
Recycling of bile acids and salts	1	200.3×	0.013	ABCB11
Transport of small molecules	2	16.8×	0.013	ATP8B1, ABCB4
Bile acid and bile salt metabolism	1	165.5×	0.013	ABCB11
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	152.3×	0.013	ABCB11
Synthesis of bile acids and bile salts	1	135.9×	0.013	ABCB11
Ion transport by P-type ATPases	1	69.2×	0.024	ATP8B1
Disease	2	8.7×	0.025	ABCB11, ABCB4
Regulation of lipid metabolism by PPARalpha	1	47.0×	0.026	ABCB4
Metabolism of steroids	1	45.9×	0.026	ABCB11
Metabolism	2	7.7×	0.026	ABCB11, ABCB4
ABC-family protein mediated transport	1	40.5×	0.028	ABCB4
Ion channel transport	1	32.0×	0.031	ATP8B1
PPARA activates gene expression	1	31.5×	0.031	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
bile acid metabolic process	2	660.9×	5e-05	ATP8B1, ABCB11
xenobiotic transmembrane transport	2	624.1×	5e-05	ATP8B1, ABCB11
bile acid and bile salt transport	2	432.1×	6e-05	ATP8B1, ABCB11
phospholipid translocation	2	416.1×	6e-05	ATP8B1, ABCB4
lipid homeostasis	2	224.7×	2e-04	ABCB11, ABCB4
transmembrane transport	2	112.3×	6e-04	ABCB11, ABCB4
canalicular bile acid transport	1	5617.3×	7e-04	ABCB11
positive regulation of bile acid secretion	1	5617.3×	7e-04	ABCB11
regulation of plasma membrane organization	1	5617.3×	7e-04	ATP8B1
response to fenofibrate	1	2808.7×	0.001	ABCB4
xenobiotic export from cell	1	1872.4×	0.002	ABCB11
obsolete regulation of bile acid metabolic process	1	1872.4×	0.002	ABCB11
positive regulation of phospholipid translocation	1	1404.3×	0.002	ABCB4
cellular response to bile acid	1	1404.3×	0.002	ABCB4
regulation of chloride transport	1	1404.3×	0.002	ATP8B1
vestibulocochlear nerve formation	1	1123.5×	0.002	ATP8B1
bile acid secretion	1	1123.5×	0.002	ABCB4
regulation of fatty acid beta-oxidation	1	936.2×	0.002	ABCB11
positive regulation of cholesterol transport	1	802.5×	0.002	ABCB4
regulation of microvillus assembly	1	802.5×	0.002	ATP8B1
inner ear receptor cell development	1	802.5×	0.002	ATP8B1
positive regulation of phospholipid transport	1	802.5×	0.002	ABCB4
apical protein localization	1	330.4×	0.004	ATP8B1
phospholipid homeostasis	1	330.4×	0.004	ABCB11
bile acid biosynthetic process	1	208.1×	0.007	ABCB11
monoatomic ion transmembrane transport	1	69.3×	0.019	ATP8B1
fatty acid metabolic process	1	64.6×	0.019	ABCB11
cholesterol homeostasis	1	52.0×	0.023	ABCB11
xenobiotic metabolic process	1	49.7×	0.023	ABCB11
Golgi organization	1	44.6×	0.025	ATP8B1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
ABCB4	1	2
ATP8B1	0	0
ATP8B1-AS1	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): 1.

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

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP8B1	7.6.2.1	P-type phospholipid transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	2	ATP8B1, ATP8B1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ATP8B1	0	ABCB11, ABCB4
ATP8B1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.