Progressive familial intrahepatic cholestasis type 2

Summary

Progressive familial intrahepatic cholestasis type 2 (MONDO:0011156) is a disease caused by ABCB11 (GenCC Definitive), with 2 cohort genes and 1 clinical trial. Top therapeutic interventions include odevixibat.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Causal gene: ABCB11 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 565
• 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 2
Mondo ID	MONDO:0011156
OMIM	601847
Orphanet	79304
DOID	DOID:0070222
ICD-11	1168921980
UMLS	C3489789
MedGen	483742
GARD	0001288
Is cancer (heuristic)	no

Also known as: ABCB11 progressive familial intrahepatic cholestasis · BSEP deficiency · cholestasis, progressive familial intrahepatic 2 · cholestasis, progressive familial intrahepatic, 2 · cholestasis, progressive familial intrahepatic, type 2 · PFIC2 · progressive familial intrahepatic cholestasis caused by mutation in ABCB11 · progressive familial intrahepatic cholestasis type 2 · severe ABCB11 deficiency

Data availability: 565 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hepatobiliary disorder › liver disorder › familial intrahepatic cholestasis › benign recurrent intrahepatic cholestasis › benign recurrent intrahepatic cholestasis type 2 › progressive familial intrahepatic cholestasis type 2

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

565 retrieved; paginated sample, class counts are floors:

189 uncertain significance, 122 conflicting classifications of pathogenicity, 67 likely pathogenic, 65 pathogenic/likely pathogenic, 53 pathogenic, 29 likely benign, 28 benign, 11 benign/likely benign, 1 benign; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
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
1345274	NM_003742.4(ABCB11):c.150+2T>C	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
1444576	NM_003742.4(ABCB11):c.3804del (p.Thr1269fs)	ABCB11	Pathogenic/Likely 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
1451287	NM_003742.4(ABCB11):c.664C>T (p.Gln222Ter)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451770	NM_003742.4(ABCB11):c.3659_3660del (p.Leu1219_Ser1220insTer)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452809	NM_003742.4(ABCB11):c.2256G>A (p.Trp752Ter)	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
1454766	NM_003742.4(ABCB11):c.164C>A (p.Ser55Ter)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456442	NM_003742.4(ABCB11):c.959_960del (p.Ile320fs)	ABCB11	Pathogenic/Likely 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
1526090	NM_003742.4(ABCB11):c.1405C>T (p.Gln469Ter)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526232	NM_003742.4(ABCB11):c.2451del (p.Tyr818fs)	ABCB11	Pathogenic	criteria provided, single submitter
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
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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
ABCB11	Definitive	Autosomal recessive	progressive familial intrahepatic cholestasis type 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
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

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
ABCB11	HGNC:42	ENSG00000073734	O95342	Bile salt export pump	gencc,clinvar
ATP8B1	HGNC:3706	ENSG00000081923	O43520	Phospholipid-transporting ATPase IC	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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…
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.

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
Transcription factor	1	4.1×	0.228

Per-gene assignment

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

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
liver	1
right lobe of liver	1
thymus	1
cardia of stomach	1
nipple	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCB11	125	tissue_specific	marker	right lobe of liver, liver, thymus
ATP8B1	289	ubiquitous	marker	cardia of stomach, nipple, renal medulla

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCB11	2,407
ATP8B1	1,296

Intra-cohort edges

A	B	Sources
ABCB11	ATP8B1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP8B1	O43520	13
ABCB11	O95342	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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×	0.002	ABCB11
Recycling of bile acids and salts	1	300.5×	0.011	ABCB11
Bile acid and bile salt metabolism	1	248.3×	0.011	ABCB11
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	228.4×	0.011	ABCB11
ABC transporter disorders	1	219.6×	0.011	ABCB11
Synthesis of bile acids and bile salts	1	203.9×	0.011	ABCB11
Ion transport by P-type ATPases	1	103.8×	0.019	ATP8B1
Disorders of transmembrane transporters	1	69.6×	0.023	ABCB11
Metabolism of steroids	1	68.8×	0.023	ABCB11
Ion channel transport	1	48.0×	0.029	ATP8B1
Metabolism of lipids	1	15.8×	0.079	ABCB11
Transport of small molecules	1	12.6×	0.091	ATP8B1
Disease	1	6.5×	0.158	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
bile acid metabolic process	2	991.3×	1e-05	ABCB11, ATP8B1
xenobiotic transmembrane transport	2	936.2×	1e-05	ABCB11, ATP8B1
bile acid and bile salt transport	2	648.1×	2e-05	ABCB11, ATP8B1
canalicular bile acid transport	1	8426.0×	5e-04	ABCB11
positive regulation of bile acid secretion	1	8426.0×	5e-04	ABCB11
regulation of plasma membrane organization	1	8426.0×	5e-04	ATP8B1
xenobiotic export from cell	1	2808.7×	0.001	ABCB11
obsolete regulation of bile acid metabolic process	1	2808.7×	0.001	ABCB11
regulation of chloride transport	1	2106.5×	0.001	ATP8B1
vestibulocochlear nerve formation	1	1685.2×	0.002	ATP8B1
regulation of fatty acid beta-oxidation	1	1404.3×	0.002	ABCB11
regulation of microvillus assembly	1	1203.7×	0.002	ATP8B1
inner ear receptor cell development	1	1203.7×	0.002	ATP8B1
apical protein localization	1	495.6×	0.004	ATP8B1
phospholipid homeostasis	1	495.6×	0.004	ABCB11
bile acid biosynthetic process	1	312.1×	0.005	ABCB11
phospholipid translocation	1	312.1×	0.005	ATP8B1
lipid homeostasis	1	168.5×	0.009	ABCB11
monoatomic ion transmembrane transport	1	104.0×	0.014	ATP8B1
fatty acid metabolic process	1	96.8×	0.014	ABCB11
transmembrane transport	1	84.3×	0.015	ABCB11
cholesterol homeostasis	1	78.0×	0.016	ABCB11
xenobiotic metabolic process	1	74.6×	0.016	ABCB11
Golgi organization	1	66.9×	0.017	ATP8B1
sensory perception of sound	1	50.5×	0.021	ATP8B1
protein ubiquitination	1	20.7×	0.050	ABCB11
negative regulation of DNA-templated transcription	1	15.8×	0.062	ATP8B1

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
ATP8B1	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

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP8B1	7.6.2.1	P-type phospholipid transporter

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	ATP8B1

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)
ATP8B1	0	ABCB11

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03566238	PHASE3	COMPLETED	This Study Will Investigate the Efficacy and Safety of A4250 in Children With PFIC Types 1 or 2

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ODEVIXIBAT	4	1