Cholestasis, intrahepatic, of pregnancy, 1

Summary

Cholestasis, intrahepatic, of pregnancy, 1 (MONDO:0007829) is a disease caused by ATP8B1 (GenCC Strong), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: ATP8B1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 47
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cholestasis, intrahepatic, of pregnancy, 1
Mondo ID	MONDO:0007829
OMIM	147480
DOID	DOID:0070228
UMLS	C3549845
MedGen	762759
GARD	0015079
Is cancer (heuristic)	no

Also known as: cholestasis, intrahepatic, of pregnancy, 1 · cholestasis, intrahepatic, of pregnancy, type 1 · ICP1

Data availability: 47 ClinVar variants · 2 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 › cholestasis, intrahepatic, of pregnancy, 1

Related subtypes (3): 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

47 retrieved; paginated sample, class counts are floors:

9 benign, 9 uncertain significance, 8 conflicting classifications of pathogenicity, 8 likely pathogenic, 7 pathogenic/likely pathogenic, 4 benign/likely benign, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4072093	Single allele	ALPK2	Pathogenic	criteria provided, single submitter
1698811	NM_001374385.1(ATP8B1):c.1573C>T (p.Arg525Ter)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
2690550	NM_001374385.1(ATP8B1):c.136C>T (p.Arg46Ter)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2736747	NM_001374385.1(ATP8B1):c.1336G>A (p.Gly446Arg)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2736748	NM_001374385.1(ATP8B1):c.886C>T (p.Arg296Cys)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3065818	NM_001374385.1(ATP8B1):c.698+1G>T	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4072081	NM_001374385.1(ATP8B1):c.958_967del (p.Met320fs)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
7267	NM_001374385.1(ATP8B1):c.1982T>C (p.Ile661Thr)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
918158	NM_001374385.1(ATP8B1):c.1581CTT[2] (p.Phe529del)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3068233	NM_001374385.1(ATP8B1):c.886C>A (p.Arg296Ser)	ATP8B1	Likely pathogenic	criteria provided, single submitter
3583374	NM_001374385.1(ATP8B1):c.2209+1del	ATP8B1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3583377	NM_001374385.1(ATP8B1):c.445del (p.Val150fs)	ATP8B1	Likely pathogenic	criteria provided, single submitter
4277624	NM_001374385.1(ATP8B1):c.637C>A (p.Leu213Ile)	ATP8B1	Likely pathogenic	criteria provided, single submitter
804427	NM_001374385.1(ATP8B1):c.2251G>T (p.Glu751Ter)	ATP8B1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3583371	NM_001374385.1(ATP8B1):c.3282T>A (p.Tyr1094Ter)	ATP8B1-AS1	Likely pathogenic	criteria provided, single submitter
3583373	NM_001374385.1(ATP8B1):c.2558_2559del (p.Phe853fs)	ATP8B1-AS1	Likely pathogenic	criteria provided, single submitter
3583376	NM_001374385.1(ATP8B1):c.941-2A>G	LOC126862761	Likely pathogenic	criteria provided, single submitter
198532	NM_001374385.1(ATP8B1):c.607A>G (p.Lys203Glu)	ATP8B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2439403	NM_001374385.1(ATP8B1):c.1798C>T (p.Arg600Trp)	ATP8B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2679840	NM_001374385.1(ATP8B1):c.2558T>C (p.Phe853Ser)	ATP8B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2679841	NM_001374385.1(ATP8B1):c.2989G>A (p.Val997Met)	ATP8B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3240825	NM_001374385.1(ATP8B1):c.1882C>T (p.Arg628Trp)	ATP8B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
500595	NM_001374385.1(ATP8B1):c.212G>A (p.Arg71His)	ATP8B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7263	NM_001374385.1(ATP8B1):c.2674G>A (p.Gly892Arg)	ATP8B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
7271	NM_001374385.1(ATP8B1):c.208G>A (p.Asp70Asn)	ATP8B1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2501792	NM_001374385.1(ATP8B1):c.2164G>C (p.Ala722Pro)	ATP8B1	Uncertain significance	criteria provided, single submitter
3064870	NM_001374385.1(ATP8B1):c.68C>T (p.Pro23Leu)	ATP8B1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3362710	NM_001374385.1(ATP8B1):c.1594G>A (p.Ala532Thr)	ATP8B1	Uncertain significance	criteria provided, multiple submitters, no conflicts
383293	NM_001374385.1(ATP8B1):c.2546G>A (p.Arg849Gln)	ATP8B1	Uncertain significance	criteria provided, multiple submitters, no conflicts
498425	NM_001374385.1(ATP8B1):c.1981A>G (p.Ile661Val)	ATP8B1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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
ATP8B1	Definitive	Autosomal recessive	progressive familial intrahepatic cholestasis type 1	7

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

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATP8B1	HGNC:3706	ENSG00000081923	O43520	Phospholipid-transporting ATPase IC	gencc,clinvar
ALPK2	HGNC:20565	ENSG00000198796	Q86TB3	Alpha-protein kinase 2	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.
ALPK2	Alpha-protein kinase 2	Protein kinase that recognizes phosphorylation sites in which the surrounding peptides have an alpha-helical conformation.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.313
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

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
ALPK2	Kinase	yes		Ig_sub2, Ig_sub, a-kinase_dom
ATP8B1-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardia of stomach	1
nipple	1
renal medulla	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
myocardium	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
ALPK2	147	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
ATP8B1-AS1	199		marker	buccal mucosa cell, primordial germ cell in gonad, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP8B1	1,296
ALPK2	371
ATP8B1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP8B1	O43520	13

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALPK2	Q86TB3	40.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 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
Ion transport by P-type ATPases	1	207.6×	0.014	ATP8B1
Ion channel transport	1	96.0×	0.016	ATP8B1
Transport of small molecules	1	25.1×	0.040	ATP8B1

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
negative regulation of Wnt signaling pathway involved in heart development	1	8426.0×	0.001	ALPK2
regulation of plasma membrane organization	1	8426.0×	0.001	ATP8B1
epicardium morphogenesis	1	4213.0×	0.002	ALPK2
regulation of chloride transport	1	2106.5×	0.002	ATP8B1
vestibulocochlear nerve formation	1	1685.2×	0.002	ATP8B1
regulation of microvillus assembly	1	1203.7×	0.002	ATP8B1
inner ear receptor cell development	1	1203.7×	0.002	ATP8B1
bile acid metabolic process	1	495.6×	0.004	ATP8B1
apical protein localization	1	495.6×	0.004	ATP8B1
xenobiotic transmembrane transport	1	468.1×	0.004	ATP8B1
bile acid and bile salt transport	1	324.1×	0.005	ATP8B1
phospholipid translocation	1	312.1×	0.005	ATP8B1
cardiac muscle cell development	1	312.1×	0.005	ALPK2
establishment of cell polarity	1	191.5×	0.007	ALPK2
heart morphogenesis	1	187.2×	0.007	ALPK2
monoatomic ion transmembrane transport	1	104.0×	0.013	ATP8B1
Golgi organization	1	66.9×	0.018	ATP8B1
sensory perception of sound	1	50.5×	0.023	ATP8B1
regulation of gene expression	1	41.7×	0.025	ALPK2
regulation of apoptotic process	1	41.7×	0.025	ALPK2
negative regulation of DNA-templated transcription	1	15.8×	0.062	ATP8B1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP8B1	0	0
ALPK2	0	0
ATP8B1-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 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: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ALPK2
E	Difficult family or no structure, no drug	2	ATP8B1, ATP8B1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ATP8B1	0	—
ALPK2	0	—
ATP8B1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03428555	Not specified	UNKNOWN	Integrated Care Pathway for Youth Depression