Congenital bile acid synthesis defect 4

Summary

Congenital bile acid synthesis defect 4 (MONDO:0008967) is a disease caused by AMACR (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AMACR (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 16
• Phenotypes (HPO): 27

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000580	Pigmentary retinopathy	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001298	Encephalopathy	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Occasional (5-29%)
HP:0005978	Type II diabetes mellitus	Occasional (5-29%)
HP:0011892	Low levels of vitamin K	Occasional (5-29%)
HP:0030516	Homonymous hemianopia	Occasional (5-29%)
HP:0100753	Schizophrenia	Occasional (5-29%)
HP:0200084	Giant cell hepatitis	Occasional (5-29%)
HP:0000135	Hypogonadism	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000763	Sensory neuropathy	Occasional (5-29%)
HP:0001081	Cholelithiasis	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0002076	Migraine	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002401	Stroke-like episode	Occasional (5-29%)
HP:0002573	Hematochezia	Occasional (5-29%)
HP:0002611	Cholestatic liver disease	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0003201	Rhabdomyolysis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital bile acid synthesis defect 4
Mondo ID	MONDO:0008967
MeSH	C535444
OMIM	214950
Orphanet	79095
DOID	DOID:0111068
UMLS	C1858328
MedGen	388039
GARD	0010046
Is cancer (heuristic)	no

Also known as: 2-methylacyl-CoA racemase deficiency · Alpha-methyl-acyl-CoA racemase deficiency · AMACR deficiency · BAS defect type 4 · BASD4 · bile acid synthesis defect, congenital, 4 · bile acid synthesis defect, congenital, type 4 · CBAS4 · cholestasis, intrahepatic, with defective conversion of · congenital bile acid synthesis defect 4 · congenital bile acid synthesis defect type 4 · liver disease-retinitis pigmentosa-polyneuropathy-epilepsy syndrome · Trihydroxycoprostanic acid to cholic acid

Data availability: 16 ClinVar variants · 2 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 › peroxisomal disease › peroxisomal single enzyme/protein defect › disorder of peroxisomal beta oxidation › alpha-methylacyl-CoA racemase deficiency › congenital bile acid synthesis defect 4

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

16 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 4 benign, 3 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
5524	NM_014324.6(AMACR):c.320T>C (p.Leu107Pro)	AMACR	Pathogenic	no assertion criteria provided
5523	NM_014324.6(AMACR):c.154T>C (p.Ser52Pro)	C1QTNF3-AMACR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
210135	NM_014324.6(AMACR):c.844G>C (p.Glu282Gln)	C1QTNF3-AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
502794	NM_014324.6(AMACR):c.783G>A (p.Met261Ile)	C1QTNF3-AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1413911	NM_014324.6(AMACR):c.887C>T (p.Pro296Leu)	AMACR	Uncertain significance	criteria provided, multiple submitters, no conflicts
502170	NM_014324.6(AMACR):c.410G>A (p.Gly137Asp)	AMACR	Uncertain significance	criteria provided, multiple submitters, no conflicts
597697	NM_014324.6(AMACR):c.511C>T (p.Arg171Cys)	AMACR	Uncertain significance	criteria provided, multiple submitters, no conflicts
596449	NM_014324.6(AMACR):c.182G>C (p.Arg61Pro)	C1QTNF3-AMACR	Uncertain significance	criteria provided, multiple submitters, no conflicts
977348	NM_014324.6(AMACR):c.*760C>T	C1QTNF3-AMACR	Uncertain significance	criteria provided, single submitter
128356	NM_014324.6(AMACR):c.25G>A (p.Val9Met)	AMACR	Benign	criteria provided, multiple submitters, no conflicts
128357	NM_014324.6(AMACR):c.524G>A (p.Gly175Asp)	AMACR	Benign	criteria provided, multiple submitters, no conflicts
128358	NM_014324.6(AMACR):c.602T>C (p.Leu201Ser)	AMACR	Benign	criteria provided, multiple submitters, no conflicts
128360	NM_014324.6(AMACR):c.829G>A (p.Glu277Lys)	AMACR	Benign	criteria provided, multiple submitters, no conflicts
353244	NM_014324.6(AMACR):c.*663G>A	AMACR	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
353245	NM_014324.6(AMACR):c.*617G>T	AMACR	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
235412	NM_014324.6(AMACR):c.782T>C (p.Met261Thr)	C1QTNF3-AMACR	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
AMACR	Strong	Autosomal recessive	congenital bile acid synthesis defect 4	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AMACR	Orphanet:79095	Congenital bile acid synthesis defect type 4

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AMACR	HGNC:451	ENSG00000242110	Q9UHK6	Alpha-methylacyl-CoA racemase	gencc,clinvar
C1QTNF3-AMACR	HGNC:49198	ENSG00000273294		C1QTNF3-AMACR readthrough (NMD candidate)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AMACR	Alpha-methylacyl-CoA racemase	Catalyzes the interconversion of (R)- and (S)-stereoisomers of alpha-methyl-branched-chain fatty acyl-CoA esters.

Protein-family classification

Druggable: 1 · Difficult: 0 · 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)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AMACR	Enzyme (other)	yes	5.1.99.4	CoA-Trfase_fam_III, CoA-Trfase_III_dom_1_sf, CoA-Trfase_III_dom3_sf
C1QTNF3-AMACR	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adult mammalian kidney	1
kidney	1
rectum	1
granulocyte	1
stromal cell of endometrium	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AMACR	134	ubiquitous	marker	adult mammalian kidney, rectum, kidney
C1QTNF3-AMACR	129		yes	ventricular zone, stromal cell of endometrium, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AMACR	1,602
C1QTNF3-AMACR	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AMACR	Q9UHK6	95.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 2 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	AMACR
Synthesis of bile acids and bile salts via 24-hydroxycholesterol	1	878.5×	0.005	AMACR
Peroxisomal lipid metabolism	1	671.8×	0.005	AMACR
Bile acid and bile salt metabolism	1	496.5×	0.005	AMACR
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	456.8×	0.005	AMACR
Synthesis of bile acids and bile salts	1	407.9×	0.005	AMACR
Protein localization	1	190.3×	0.009	AMACR
Peroxisomal protein import	1	173.0×	0.009	AMACR
Metabolism of steroids	1	137.6×	0.009	AMACR
Fatty acid metabolism	1	131.3×	0.009	AMACR
Metabolism of lipids	1	31.6×	0.035	AMACR
Metabolism	1	11.6×	0.086	AMACR

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	AMACR
bile acid metabolic process	1	991.3×	0.002	AMACR
bile acid biosynthetic process	1	624.1×	0.002	AMACR

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
AMACR	0	0
C1QTNF3-AMACR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AMACR	5.1.99.4	alpha-methylacyl-CoA racemase

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	1	AMACR
E	Difficult family or no structure, no drug	1	C1QTNF3-AMACR

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AMACR	0	—
C1QTNF3-AMACR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.