Congenital bile acid synthesis defect 6

Summary

Congenital bile acid synthesis defect 6 (MONDO:0015015) is a disease caused by ACOX2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ACOX2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital bile acid synthesis defect 6
Mondo ID	MONDO:0015015
OMIM	617308
DOID	DOID:0111067
UMLS	C4310624
MedGen	934591
GARD	0025050
Is cancer (heuristic)	no

Also known as: ACOX2 congenital bile acid synthesis defect · bile acid synthesis defect, congenital, 6 · bile acid synthesis defect, congenital, type 6 · CBAS6 · congenital bile acid synthesis defect caused by mutation in ACOX2 · congenital bile acid synthesis defect type 6

Data availability: 15 ClinVar variants · 4 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 › inherited lipid metabolism disorder › steroid inherited metabolic disorder › congenital bile acid synthesis defect › congenital bile acid synthesis defect 6

Related subtypes (5): congenital bile acid synthesis defect 4, congenital bile acid synthesis defect 2, congenital bile acid synthesis defect 1, congenital bile acid synthesis defect 3, congenital bile acid synthesis defect 5

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

15 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 4 conflicting classifications of pathogenicity, 3 benign, 1 likely benign, 1 benign/likely benign, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
375219	NM_003500.4(ACOX2):c.207T>A (p.Tyr69Ter)	ACOX2	Pathogenic	no assertion criteria provided
4849335	NM_003500.4(ACOX2):c.674G>A (p.Arg225Gln)	ACOX2	Likely pathogenic	criteria provided, single submitter
1687262	NM_003500.4(ACOX2):c.323+2T>C	ACOX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2438827	NM_003500.4(ACOX2):c.1720C>T (p.Arg574Cys)	ACOX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
375691	NM_003500.4(ACOX2):c.673C>T (p.Arg225Trp)	ACOX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
710623	NM_003500.4(ACOX2):c.461_464del (p.Thr154fs)	ACOX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1034006	NM_003500.4(ACOX2):c.380G>A (p.Arg127Lys)	ACOX2	Uncertain significance	criteria provided, single submitter
3362352	NM_003500.4(ACOX2):c.749C>T (p.Thr250Ile)	ACOX2	Uncertain significance	criteria provided, single submitter
3603299	NM_003500.4(ACOX2):c.1983+2T>C	ACOX2	Uncertain significance	criteria provided, single submitter
562218	NM_003500.4(ACOX2):c.149G>A (p.Arg50His)	ACOX2	Uncertain significance	criteria provided, single submitter
1188891	NM_003500.4(ACOX2):c.161-57C>G	ACOX2	Benign	criteria provided, multiple submitters, no conflicts
1188892	NM_003500.4(ACOX2):c.-26T>C	ACOX2	Benign	criteria provided, multiple submitters, no conflicts
1301652	NM_003500.4(ACOX2):c.182C>T (p.Pro61Leu)	ACOX2	Likely benign	criteria provided, multiple submitters, no conflicts
1618094	NM_003500.4(ACOX2):c.475+18C>T	ACOX2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
3338234	NM_003500.4(ACOX2):c.373G>A (p.Ala125Thr)	ACOX2	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 0 · 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
ACOX2	Definitive	Autosomal recessive	congenital bile acid synthesis defect 6	4

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
ACOX2	HGNC:120	ENSG00000168306	Q99424	Peroxisomal acyl-coenzyme A oxidase 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACOX2	Peroxisomal acyl-coenzyme A oxidase 2	Oxidizes the CoA esters of the bile acid intermediates di- and tri-hydroxycholestanoic acids.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACOX2	Other/Unknown	no		Acyl-CoA_oxidase_C, AcylCoA_DH/oxidase_NM_dom_sf, Acyl-CoA_oxidase

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
liver	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACOX2	223	ubiquitous	marker	right lobe of liver, male germ line stem cell (sensu Vertebrata) in testis, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACOX2	2,309

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACOX2	Q99424	94.49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Beta-oxidation of pristanoyl-CoA	1	1142.0×	0.005	ACOX2
Peroxisomal lipid metabolism	1	671.8×	0.005	ACOX2
Bile acid and bile salt metabolism	1	496.5×	0.005	ACOX2
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	456.8×	0.005	ACOX2
Synthesis of bile acids and bile salts	1	407.9×	0.005	ACOX2
Protein localization	1	190.3×	0.009	ACOX2
Peroxisomal protein import	1	173.0×	0.009	ACOX2
Metabolism of steroids	1	137.6×	0.009	ACOX2
Fatty acid metabolism	1	131.3×	0.009	ACOX2
Metabolism of lipids	1	31.6×	0.035	ACOX2
Metabolism	1	11.6×	0.086	ACOX2

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
fatty acid beta-oxidation using acyl-CoA oxidase	1	1123.5×	0.002	ACOX2
very long-chain fatty acid metabolic process	1	766.0×	0.002	ACOX2
bile acid biosynthetic process	1	624.1×	0.002	ACOX2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
ACOX2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
E	Difficult family or no structure, no drug	1	ACOX2

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)
ACOX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.