Hypercholanemia, familial 1

Summary

Hypercholanemia, familial 1 (MONDO:0031446) is a disease caused by BAAT (GenCC Strong), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: BAAT (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 118

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		23	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hypercholanemia, familial 1
Mondo ID	MONDO:0031446
MeSH	C564336
OMIM	607748
Orphanet	238475
DOID	DOID:0061181
SNOMED CT	723360007
UMLS	C5542604
MedGen	1781366
GARD	0017173
Is cancer (heuristic)	no

Also known as: FHCA1 · hereditary hypercholanemia

Data availability: 118 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of bile acid synthesis › hypercholanemia, familial › hypercholanemia, familial 1

Related subtypes (1): hypercholanemia, familial, 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

118 retrieved; paginated sample, class counts are floors:

61 uncertain significance, 29 benign, 12 conflicting classifications of pathogenicity, 7 likely benign, 4 benign/likely benign, 2 pathogenic, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
139629	NM_004817.4(TJP2):c.1361del (p.Ala454fs)	TJP2	Pathogenic	criteria provided, single submitter
2907	NM_004817.4(TJP2):c.143T>C (p.Val48Ala)	TJP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632045	NM_004817.4(TJP2):c.1894C>T (p.Arg632Ter)	TJP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1693162	NM_020812.4(DOCK6):c.3895-48_3895-47del	DOCK6	Likely pathogenic	no assertion criteria provided
3382765	NM_004817.4(TJP2):c.953-2A>G	TJP2	Likely pathogenic	criteria provided, single submitter
289950	NM_001701.4(BAAT):c.997A>G (p.Ser333Gly)	BAAT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1213131	NM_004817.4(TJP2):c.2081G>A (p.Gly694Glu)	TJP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1309993	NM_004817.4(TJP2):c.853C>T (p.Arg285Cys)	TJP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1343078	NM_004817.4(TJP2):c.2044C>T (p.Arg682Trp)	TJP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1359622	NM_004817.4(TJP2):c.899G>A (p.Arg300Lys)	TJP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
139627	NM_004817.4(TJP2):c.766_769del (p.Ala256fs)	TJP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
165403	NM_004817.4(TJP2):c.185C>T (p.Thr62Met)	TJP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178543	NM_004817.4(TJP2):c.1258C>T (p.Arg420Cys)	TJP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178813	NM_004817.4(TJP2):c.1213_1215del (p.Ile405del)	TJP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
367224	NM_004817.4(TJP2):c.1960T>C (p.Leu654=)	TJP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
367235	NM_004817.4(TJP2):c.3371C>T (p.Thr1124Met)	TJP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
489223	NM_004817.4(TJP2):c.1056+2T>C	TJP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191236	NM_001701.4(BAAT):c.761C>T (p.Thr254Met)	BAAT	Uncertain significance	criteria provided, multiple submitters, no conflicts
364247	NM_001701.4(BAAT):c.*1890C>A	BAAT	Uncertain significance	criteria provided, single submitter
364252	NM_001701.4(BAAT):c.*1575T>G	BAAT	Uncertain significance	criteria provided, single submitter
364256	NM_001701.4(BAAT):c.*1218A>G	BAAT	Uncertain significance	criteria provided, single submitter
364260	NM_001701.4(BAAT):c.*1139T>G	BAAT	Uncertain significance	criteria provided, single submitter
364261	NM_001701.4(BAAT):c.*1136A>G	BAAT	Uncertain significance	criteria provided, single submitter
364264	NM_001701.4(BAAT):c.*1030T>A	BAAT	Uncertain significance	criteria provided, single submitter
364273	NM_001701.4(BAAT):c.*199A>T	BAAT	Uncertain significance	criteria provided, single submitter
364276	NM_001701.4(BAAT):c.1135G>A (p.Asp379Asn)	BAAT	Uncertain significance	criteria provided, single submitter
364278	NM_001701.4(BAAT):c.780C>T (p.Thr260=)	BAAT	Uncertain significance	criteria provided, single submitter
364279	NM_001701.4(BAAT):c.473G>T (p.Gly158Val)	BAAT	Uncertain significance	criteria provided, single submitter
364281	NM_001701.4(BAAT):c.264A>G (p.Leu88=)	BAAT	Uncertain significance	criteria provided, single submitter
364282	NM_001701.4(BAAT):c.178C>T (p.Leu60=)	BAAT	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
BAAT	Strong	Autosomal recessive	hypercholanemia, familial 1	5
TJP2	Supportive	Autosomal recessive	familial hypercholanemia	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TJP2	Orphanet:238475	Familial hypercholanemia
TJP2	Orphanet:480483	Progressive familial intrahepatic cholestasis type 4
TJP2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
BAAT	Orphanet:238475	Familial hypercholanemia
DOCK6	Orphanet:974	Adams-Oliver syndrome
EPHX1	Orphanet:238475	Familial hypercholanemia

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TJP2	HGNC:11828	ENSG00000119139	Q9UDY2	Tight junction protein 2	gencc,clinvar
BAAT	HGNC:932	ENSG00000136881	Q14032	Bile acid-CoA:amino acid N-acyltransferase	gencc,clinvar
DOCK6	HGNC:19189	ENSG00000130158	Q96HP0	Dedicator of cytokinesis protein 6	clinvar
EPHX1	HGNC:3401	ENSG00000143819	P07099	Epoxide hydrolase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TJP2	Tight junction protein 2	Plays a role in tight junctions and adherens junctions.
BAAT	Bile acid-CoA:amino acid N-acyltransferase	Catalyzes the amidation of bile acids (BAs) with the amino acids taurine and glycine.
DOCK6	Dedicator of cytokinesis protein 6	Acts as a guanine nucleotide exchange factor (GEF) for CDC42 and RAC1 small GTPases.
EPHX1	Epoxide hydrolase 1	Biotransformation enzyme that catalyzes the hydrolysis of arene and aliphatic epoxides to less reactive and more water soluble dihydrodiols by the trans addition of water.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · 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
Enzyme (other)	2	6.0×	0.112
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TJP2	Scaffold/PPI	no		SH3_domain, PDZ, ZO
BAAT	Enzyme (other)	yes	2.3.1.65	Thio_Ohase/aa_AcTrfase, BAAT_C, Acyl-CoA_thioEstase_long-chain
DOCK6	Other/Unknown	no		DOCK_C/D_N, DOCK, C2_DOCK-type_domain
EPHX1	Enzyme (other)	yes	3.3.2.9	AB_hydrolase_1, Epox_hydrolase-like, Epoxide_hydrolase

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus callosum	1
descending thoracic aorta	1
thoracic aorta	1
gall bladder	1
liver	1
right lobe of liver	1
apex of heart	1
colonic epithelium	1
right lung	1
adrenal cortex	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TJP2	134	ubiquitous	marker	corpus callosum, descending thoracic aorta, thoracic aorta
BAAT	105	tissue_specific	marker	liver, right lobe of liver, gall bladder
DOCK6	254	ubiquitous	marker	colonic epithelium, right lung, apex of heart
EPHX1	276	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, adrenal cortex

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TJP2	2,916
EPHX1	2,678
DOCK6	1,018
BAAT	964

Intra-cohort edges

A	B	Sources
BAAT	EPHX1	string_interaction
BAAT	TJP2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DOCK6	Q96HP0	7
TJP2	Q9UDY2	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BAAT	Q14032	95.31
EPHX1	P07099	95.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Apoptotic cleavage of cell adhesion proteins	1	259.6×	0.029	TJP2
Recycling of bile acids and salts	1	150.3×	0.029	BAAT
Signaling by Hippo	1	135.9×	0.029	TJP2
Bile acid and bile salt metabolism	1	124.1×	0.029	BAAT
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	114.2×	0.029	BAAT
Synthesis of bile acids and bile salts	1	102.0×	0.029	BAAT
Phase I - Functionalization of compounds	1	54.9×	0.043	EPHX1
Protein localization	1	47.6×	0.043	BAAT
Peroxisomal protein import	1	43.3×	0.043	BAAT
RHOB GTPase cycle	1	38.6×	0.043	TJP2
RHOC GTPase cycle	1	36.6×	0.043	TJP2
Metabolism of steroids	1	34.4×	0.043	BAAT
RHOA GTPase cycle	1	18.7×	0.070	TJP2
CDC42 GTPase cycle	1	18.1×	0.070	DOCK6
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.071	DOCK6
RAC1 GTPase cycle	1	15.3×	0.072	DOCK6
Metabolism of lipids	1	7.9×	0.128	BAAT
Metabolism	1	2.9×	0.302	BAAT

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 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 conjugation	1	4213.0×	0.003	BAAT
hydrocarbon catabolic process	1	4213.0×	0.003	EPHX1
epoxide metabolic process	1	1404.3×	0.006	EPHX1
positive regulation of blood-brain barrier permeability	1	842.6×	0.006	TJP2
glycine metabolic process	1	702.2×	0.006	BAAT
taurine metabolic process	1	702.2×	0.006	BAAT
regulation of membrane permeability	1	601.9×	0.006	TJP2
protein localization to cell-cell junction	1	468.1×	0.007	TJP2
homotypic cell-cell adhesion	1	421.3×	0.007	TJP2
establishment of endothelial intestinal barrier	1	351.1×	0.007	TJP2
intestinal absorption	1	300.9×	0.008	TJP2
bile acid metabolic process	1	247.8×	0.008	BAAT
acyl-CoA metabolic process	1	175.5×	0.010	BAAT
bile acid biosynthetic process	1	156.0×	0.010	BAAT
cell-cell junction organization	1	156.0×	0.010	TJP2
animal organ regeneration	1	150.5×	0.010	BAAT
regulation of Rho protein signal transduction	1	127.7×	0.011	DOCK6
arachidonate metabolic process	1	120.4×	0.011	EPHX1
maintenance of blood-brain barrier	1	120.4×	0.011	TJP2
liver development	1	55.4×	0.022	BAAT
response to toxic substance	1	52.7×	0.022	EPHX1
fatty acid metabolic process	1	48.4×	0.023	BAAT
small GTPase-mediated signal transduction	1	45.8×	0.024	DOCK6
xenobiotic metabolic process	1	37.3×	0.028	EPHX1
cell-cell adhesion	1	25.4×	0.039	TJP2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EPHX1	2	2
TJP2	0	0
BAAT	0	0
DOCK6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRICLOCARBAN	2	EPHX1
AR9281	2	EPHX1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
EPHX1	30	Binding:18, ADMET:12

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BAAT	2.3.1.65	bile acid-CoA:amino acid N-acyltransferase
EPHX1	3.3.2.9	microsomal epoxide hydrolase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
TRICLOCARBAN	2	EPHX1
AR9281	2	EPHX1

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	1	EPHX1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	BAAT
E	Difficult family or no structure, no drug	2	TJP2, DOCK6

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)
TJP2	0	—
BAAT	0	—
DOCK6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.