Cholestasis, progressive familial intrahepatic, 5

Summary

Cholestasis, progressive familial intrahepatic, 5 (MONDO:0014884) is a disease caused by NR1H4 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NR1H4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	cholestasis, progressive familial intrahepatic, 5
Mondo ID	MONDO:0014884
OMIM	617049
Orphanet	480476
DOID	DOID:0070225
UMLS	C4310747
MedGen	934714
GARD	0017867
Is cancer (heuristic)	no

Also known as: cholestasis, progressive familial intrahepatic, 5 · cholestasis, progressive familial intrahepatic, 5; PFIC5 · cholestasis, progressive familial intrahepatic, type 5 · NR1H4 deficiency · NR1H4 progressive familial intrahepatic cholestasis · PFIC5 · progressive familial intrahepatic cholestasis caused by mutation in NR1H4

Data availability: 17 ClinVar variants · 2 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, 5

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, 4, 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

17 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 5 pathogenic, 4 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
219162	NM_001206979.2(NR1H4):c.419_420insAAA (p.Tyr139_Asn140insLys)	NR1H4	Pathogenic	criteria provided, single submitter
219163	NG_029843.1:g.23704_55438del	NR1H4	Pathogenic	criteria provided, single submitter
219164	NM_001206979.2(NR1H4):c.526C>T (p.Arg176Ter)	NR1H4	Pathogenic	criteria provided, multiple submitters, no conflicts
2687827	NM_001206979.2(NR1H4):c.1280del (p.Gln427fs)	NR1H4	Pathogenic	criteria provided, single submitter
3237163	NM_001206979.2(NR1H4):c.79G>T (p.Gly27Cys)	NR1H4	Pathogenic	criteria provided, single submitter
498106	NM_001206979.2(NR1H4):c.831+1G>A	NR1H4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339549	NM_001206979.2(NR1H4):c.887C>T (p.Thr296Ile)	NR1H4	Likely pathogenic	criteria provided, single submitter
1683627	NM_001206979.2(NR1H4):c.831+1G>T	NR1H4	Likely pathogenic	criteria provided, single submitter
2687828	NM_001206979.2(NR1H4):c.976G>C (p.Gly326Arg)	NR1H4	Likely pathogenic	criteria provided, single submitter
804467	NM_001206979.2(NR1H4):c.1034del (p.Pro345fs)	NR1H4	Likely pathogenic	criteria provided, single submitter
3574159	NM_001206979.2(NR1H4):c.1211A>G (p.Asp404Gly)	NR1H4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2434431	NM_001206979.2(NR1H4):c.380G>A (p.Cys127Tyr)	NR1H4	Uncertain significance	criteria provided, single submitter
3064862	NM_001206979.2(NR1H4):c.883G>T (p.Ala295Ser)	NR1H4	Uncertain significance	criteria provided, single submitter
3899390	NM_001206979.2(NR1H4):c.521A>G (p.Tyr174Cys)	NR1H4	Uncertain significance	criteria provided, single submitter
3899391	NM_001206979.2(NR1H4):c.558A>T (p.Lys186Asn)	NR1H4	Uncertain significance	criteria provided, multiple submitters, no conflicts
595191	NM_001206979.2(NR1H4):c.1A>G (p.Met1Val)	NR1H4	Uncertain significance	criteria provided, multiple submitters, no conflicts
596067	NM_001206979.2(NR1H4):c.268C>T (p.Arg90Cys)	NR1H4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 2 · 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
NR1H4	Strong	Autosomal recessive	cholestasis, progressive familial intrahepatic, 5	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NR1H4	Orphanet:480476	Progressive familial intrahepatic cholestasis type 5
NR1H4	Orphanet:69665	Intrahepatic cholestasis of pregnancy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NR1H4	HGNC:7967	ENSG00000012504	Q96RI1	Bile acid receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NR1H4	Bile acid receptor	Ligand-activated transcription factor.

Protein-family classification

Druggable: 1 · 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
Nuclear receptor	1	385.9×	0.003

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NR1H4	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NR1H4	136	tissue_specific	marker	right lobe of liver, liver, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NR1H4	3,094

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NR1H4	Q96RI1	89

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of bile acids and bile salts via 27-hydroxycholesterol	1	761.3×	0.004	NR1H4
Recycling of bile acids and salts	1	601.0×	0.004	NR1H4
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	456.8×	0.004	NR1H4
Synthesis of bile acids and bile salts	1	407.9×	0.004	NR1H4
Endogenous sterols	1	393.8×	0.004	NR1H4
SUMOylation of intracellular receptors	1	335.9×	0.004	NR1H4
Nuclear Receptor transcription pathway	1	200.3×	0.006	NR1H4
PPARA activates gene expression	1	94.4×	0.011	NR1H4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete regulation of urea metabolic process	1	16852.0×	7e-04	NR1H4
positive regulation of phosphatidic acid biosynthetic process	1	16852.0×	7e-04	NR1H4
obsolete positive regulation of glutamate metabolic process	1	16852.0×	7e-04	NR1H4
positive regulation of ammonia assimilation cycle	1	16852.0×	7e-04	NR1H4
nuclear receptor-mediated bile acid signaling pathway	1	8426.0×	0.001	NR1H4
regulation of low-density lipoprotein particle clearance	1	5617.3×	0.001	NR1H4
cellular response to bile acid	1	4213.0×	0.002	NR1H4
negative regulation of very-low-density lipoprotein particle remodeling	1	2808.7×	0.002	NR1H4
negative regulation of interleukin-1 production	1	2808.7×	0.002	NR1H4
regulation of bile acid biosynthetic process	1	2808.7×	0.002	NR1H4
negative regulation of monocyte chemotactic protein-1 production	1	2808.7×	0.002	NR1H4
toll-like receptor 9 signaling pathway	1	1872.4×	0.002	NR1H4
intracellular triglyceride homeostasis	1	1685.2×	0.002	NR1H4
regulation of cholesterol metabolic process	1	1123.5×	0.003	NR1H4
positive regulation of adipose tissue development	1	1053.2×	0.003	NR1H4
bile acid metabolic process	1	991.3×	0.003	NR1H4
intracellular receptor signaling pathway	1	991.3×	0.003	NR1H4
fatty acid homeostasis	1	936.2×	0.003	NR1H4
regulation of insulin secretion involved in cellular response to glucose stimulus	1	936.2×	0.003	NR1H4
positive regulation of insulin receptor signaling pathway	1	842.6×	0.003	NR1H4
cellular response to fatty acid	1	702.2×	0.003	NR1H4
bile acid and bile salt transport	1	648.1×	0.003	NR1H4
positive regulation of interleukin-17 production	1	601.9×	0.003	NR1H4
intracellular glucose homeostasis	1	581.1×	0.003	NR1H4
negative regulation of interleukin-2 production	1	581.1×	0.003	NR1H4
negative regulation of tumor necrosis factor-mediated signaling pathway	1	455.5×	0.004	NR1H4
cell-cell junction assembly	1	443.5×	0.004	NR1H4
negative regulation of type II interferon production	1	383.0×	0.004	NR1H4
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	374.5×	0.004	NR1H4
negative regulation of interleukin-6 production	1	351.1×	0.004	NR1H4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
NR1H4	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NR1H4	41	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	NR1H4
SIMVASTATIN	4	NR1H4
RIMONABANT	4	NR1H4
ACETAMINOPHEN	4	NR1H4
SULCONAZOLE	4	NR1H4
REPAGLINIDE	4	NR1H4
CLOFAZIMINE	4	NR1H4
FULVESTRANT	4	NR1H4
DICLOFENAC	4	NR1H4
NIMODIPINE	4	NR1H4
FELODIPINE	4	NR1H4
ATORVASTATIN	4	NR1H4
KETOCONAZOLE	4	NR1H4
CYCLOSPORINE	4	NR1H4
LEVOTHYROXINE	4	NR1H4
REGORAFENIB	4	NR1H4
CHOLIC ACID	4	NR1H4
FLUTRIMAZOLE	4	NR1H4
PRANLUKAST	4	NR1H4
CHENODIOL	4	NR1H4
TAURURSODIOL	4	NR1H4
BENZBROMARONE	4	NR1H4
DEOXYCHOLIC ACID	4	NR1H4
TROGLITAZONE	4	NR1H4
ODEVIXIBAT	4	NR1H4
SUNITINIB	4	NR1H4
EPALRESTAT	4	NR1H4
OBETICHOLIC ACID	4	NR1H4
ZAFIRLUKAST	4	NR1H4
IVERMECTIN	4	NR1H4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NR1H4	1,034	Binding:873, Functional:154, ADMET:6, Unclassified:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
NR1H4	1,034

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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)
CLOTRIMAZOLE	4	NR1H4
SIMVASTATIN	4	NR1H4
RIMONABANT	4	NR1H4
ACETAMINOPHEN	4	NR1H4
SULCONAZOLE	4	NR1H4
REPAGLINIDE	4	NR1H4
CLOFAZIMINE	4	NR1H4
FULVESTRANT	4	NR1H4
DICLOFENAC	4	NR1H4
NIMODIPINE	4	NR1H4
FELODIPINE	4	NR1H4
ATORVASTATIN	4	NR1H4
KETOCONAZOLE	4	NR1H4
CYCLOSPORINE	4	NR1H4
LEVOTHYROXINE	4	NR1H4
REGORAFENIB	4	NR1H4
CHOLIC ACID	4	NR1H4
FLUTRIMAZOLE	4	NR1H4
PRANLUKAST	4	NR1H4
CHENODIOL	4	NR1H4
TAURURSODIOL	4	NR1H4
BENZBROMARONE	4	NR1H4
DEOXYCHOLIC ACID	4	NR1H4
TROGLITAZONE	4	NR1H4
ODEVIXIBAT	4	NR1H4
SUNITINIB	4	NR1H4
EPALRESTAT	4	NR1H4
OBETICHOLIC ACID	4	NR1H4
ZAFIRLUKAST	4	NR1H4
IVERMECTIN	4	NR1H4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NR1H4
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	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.