Benign recurrent intrahepatic cholestasis type 1

Summary

Benign recurrent intrahepatic cholestasis type 1 (MONDO:0009469) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 81

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	benign recurrent intrahepatic cholestasis type 1
Mondo ID	MONDO:0009469
OMIM	243300
Orphanet	99960
DOID	DOID:0070231
UMLS	C4551899
MedGen	1637492
GARD	0010028
Is cancer (heuristic)	no

Also known as: ATP8B1 benign recurrent intrahepatic cholestasis · benign recurrent intrahepatic cholestasis 1 · benign recurrent intrahepatic cholestasis caused by mutation in ATP8B1 · Bric type 1 · BRIC1 · cholestasis, benign recurrent intrahepatic · cholestasis, benign recurrent intrahepatic 1 · cholestasis, benign recurrent intrahepatic, 1 · cholestasis, benign recurrent intrahepatic, type 1 · mild ATP8B1 deficiency · recurrent familial intrahepatic cholestasis 1 · Summerskill syndrome

Data availability: 81 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › progressive familial intrahepatic cholestasis › benign recurrent intrahepatic cholestasis type 1

Related subtypes (15): progressive familial 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, cholestasis, progressive familial intrahepatic, 5, 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

81 retrieved; paginated sample, class counts are floors:

26 likely pathogenic, 20 pathogenic/likely pathogenic, 13 pathogenic, 10 uncertain significance, 9 conflicting classifications of pathogenicity, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4072093	Single allele	ALPK2	Pathogenic	criteria provided, single submitter
126382	NM_001374385.1(ATP8B1):c.1993G>T (p.Glu665Ter)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1301678	NM_001374385.1(ATP8B1):c.3040C>T (p.Arg1014Ter)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1687187	NM_001374385.1(ATP8B1):c.1891C>T (p.Arg631Ter)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698723	NM_001374385.1(ATP8B1):c.2821C>T (p.Arg941Ter)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1698811	NM_001374385.1(ATP8B1):c.1573C>T (p.Arg525Ter)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1878254	NM_001374385.1(ATP8B1):c.922G>A (p.Gly308Ser)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2504019	NM_001374385.1(ATP8B1):c.1210_1213del (p.Leu404fs)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679844	NM_001374385.1(ATP8B1):c.3531+1G>A	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679846	NM_001374385.1(ATP8B1):c.2941G>A (p.Glu981Lys)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679849	NM_001374385.1(ATP8B1):c.2081T>A (p.Ile694Asn)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679853	NM_001374385.1(ATP8B1):c.1214_1215del (p.Tyr405fs)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
2679854	NM_001374385.1(ATP8B1):c.811A>T (p.Arg271Ter)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
2679855	NM_001374385.1(ATP8B1):c.3490C>T (p.Arg1164Ter)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679856	NM_001374385.1(ATP8B1):c.3400+2T>C	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679858	NM_001374385.1(ATP8B1):c.2418+5G>A	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679860	NM_001374385.1(ATP8B1):c.1246_1247del (p.His417fs)	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
289530	NM_001374385.1(ATP8B1):c.279G>A (p.Ala93=)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
290904	NM_001374385.1(ATP8B1):c.2286-2A>G	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2988981	NM_001374385.1(ATP8B1):c.212del (p.Arg71fs)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3240829	NM_001374385.1(ATP8B1):c.2873del (p.Asn958fs)	ATP8B1	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
502324	NM_001374385.1(ATP8B1):c.1799G>A (p.Arg600Gln)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
596167	NM_001374385.1(ATP8B1):c.614dup (p.Asn205fs)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
631804	NM_001374385.1(ATP8B1):c.2844del (p.Met947_Cys948insTer)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
7265	NM_001374385.1(ATP8B1):c.2097+2T>C	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
7270	NM_001374385.1(ATP8B1):c.2932-3C>A	ATP8B1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · 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

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
ALPK2	HGNC:20565	ENSG00000198796	Q86TB3	Alpha-protein kinase 2	clinvar
ATP8B1	HGNC:3706	ENSG00000081923	O43520	Phospholipid-transporting ATPase IC	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)
ALPK2	Alpha-protein kinase 2	Protein kinase that recognizes phosphorylation sites in which the surrounding peptides have an alpha-helical conformation.
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: 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)
ALPK2	Kinase	yes		Ig_sub2, Ig_sub, a-kinase_dom
ATP8B1	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf
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
cardiac muscle of right atrium	1
left ventricle myocardium	1
myocardium	1
cardia of stomach	1
nipple	1
renal medulla	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
ALPK2	147	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
ATP8B1	289	ubiquitous	marker	cardia of stomach, nipple, renal medulla
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
ALPK2	0	0
ATP8B1	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)
ALPK2	0	—
ATP8B1	0	—
ATP8B1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.