Cholestasis, intrahepatic, of pregnancy, 3

Summary

Cholestasis, intrahepatic, of pregnancy, 3 (MONDO:0013995) is a disease caused by ABCB4 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ABCB4 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 156

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cholestasis, intrahepatic, of pregnancy, 3
Mondo ID	MONDO:0013995
OMIM	614972
DOID	DOID:0070229
UMLS	C3554241
MedGen	767155
GARD	0015888
Is cancer (heuristic)	no

Also known as: cholestasis, intrahepatic, of pregnancy 3 · cholestasis, intrahepatic, of pregnancy type 3 · ICP3

Data availability: 156 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hepatobiliary disorder › liver disorder › familial intrahepatic cholestasis › cholestasis, intrahepatic, of pregnancy, 3

Related subtypes (3): cholestasis, intrahepatic, of pregnancy, 1, 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

156 retrieved; paginated sample, class counts are floors:

47 uncertain significance, 39 conflicting classifications of pathogenicity, 20 pathogenic, 16 pathogenic/likely pathogenic, 14 likely pathogenic, 11 benign/likely benign, 9 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
284637	NM_003742.4(ABCB11):c.2012-8T>G	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
290081	NM_003742.4(ABCB11):c.1460G>A (p.Arg487His)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6590	NM_003742.4(ABCB11):c.890A>G (p.Glu297Gly)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
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
13693	NM_000443.4(ABCB4):c.1328_1329delinsCAA (p.Gln443fs)	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
2687809	NM_000443.4(ABCB4):c.1436C>T (p.Pro479Leu)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2687818	NM_000443.4(ABCB4):c.88_91del (p.Lys30fs)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3032272	NM_000443.4(ABCB4):c.1371del (p.Gln458fs)	ABCB4	Pathogenic	criteria provided, multiple submitters, no conflicts
3391149	NM_000443.4(ABCB4):c.593del (p.Ala198fs)	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
4536822	NM_000443.4(ABCB4):c.1633C>T (p.Arg545Cys)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
500242	NM_000443.4(ABCB4):c.1015del (p.Ser339fs)	ABCB4	Pathogenic	criteria provided, multiple submitters, no conflicts
501724	NM_000443.4(ABCB4):c.3486+1G>A	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
587488	NM_000443.4(ABCB4):c.3136C>T (p.Arg1046Ter)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
596680	NM_000443.4(ABCB4):c.475C>T (p.Arg159Ter)	ABCB4	Pathogenic	criteria provided, multiple submitters, no conflicts
597760	NM_000443.4(ABCB4):c.879del (p.Ala294fs)	ABCB4	Pathogenic	criteria provided, multiple submitters, no conflicts
617459	NM_000443.4(ABCB4):c.2044del (p.Asp682fs)	ABCB4	Pathogenic	criteria provided, single submitter
812751	NM_000443.4(ABCB4):c.893del (p.Asn298fs)	ABCB4	Pathogenic	criteria provided, single submitter
812752	NM_000443.4(ABCB4):c.834-1G>A	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812753	NM_000443.4(ABCB4):c.652del (p.Leu218_Val219insTer)	ABCB4	Pathogenic	criteria provided, single submitter
812754	NM_000443.4(ABCB4):c.449G>A (p.Arg150Lys)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812921	NM_000443.4(ABCB4):c.2683-883_2783+345del	ABCB4	Pathogenic	no assertion criteria provided
812975	NM_000443.4(ABCB4):c.3535C>T (p.Gln1179Ter)	ABCB4	Pathogenic	criteria provided, single submitter

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: 0.