alpha-methylacyl-CoA racemase deficiency

Summary

alpha-methylacyl-CoA racemase deficiency (MONDO:0013681) is a disease caused by AMACR (GenCC Definitive), with 4 cohort genes and 1 clinical trial.

At a glance

• Causal gene: AMACR (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 380
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	alpha-methylacyl-CoA racemase deficiency
Mondo ID	MONDO:0013681
EFO	EFO:1001980
MeSH	C565768
OMIM	614307
DOID	DOID:0060602
NCIT	C119677
SNOMED CT	700463002
UMLS	C3280428
MedGen	482058
GARD	0015787
Is cancer (heuristic)	no

Also known as: alpha-methylacyl-CoA racemase deficiency · AMACR · AMACR deficiency · AMACRD

Data availability: 380 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

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

Related subtypes (4): d-bifunctional protein deficiency, peroxisomal acyl-CoA oxidase deficiency, sterol carrier protein 2 deficiency, acyl-CoA binding domain containing protein 5 deficiency

Subtypes (1): 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

380 retrieved; paginated sample, class counts are floors:

201 uncertain significance, 136 likely benign, 23 conflicting classifications of pathogenicity, 14 benign, 5 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
5523	NM_014324.6(AMACR):c.154T>C (p.Ser52Pro)	C1QTNF3-AMACR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1919648	NM_014324.6(AMACR):c.967G>A (p.Val323Met)	AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
235439	NM_014324.6(AMACR):c.554T>C (p.Val185Ala)	AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353253	NM_014324.6(AMACR):c.740-5C>G	AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353256	NM_014324.6(AMACR):c.48G>A (p.Pro16=)	AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
384898	NM_014324.6(AMACR):c.-22C>G	AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
387261	NM_014324.6(AMACR):c.247+8C>G	AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4705605	NM_014324.6(AMACR):c.439C>T (p.Leu147=)	AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
595976	NM_014324.6(AMACR):c.429G>A (p.Pro143=)	AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
597102	NM_014324.6(AMACR):c.247+9G>T	AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
597870	NM_014324.6(AMACR):c.714C>G (p.Pro238=)	AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
597902	NM_014324.6(AMACR):c.243C>T (p.Arg81=)	AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903704	NM_014324.6(AMACR):c.289C>A (p.Arg97=)	AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907075	NM_014324.6(AMACR):c.553-5C>A	AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907076	NM_014324.6(AMACR):c.366C>T (p.His122=)	AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1900881	NM_014324.6(AMACR):c.20C>T (p.Ser7Leu)	C1QTNF3-AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210135	NM_014324.6(AMACR):c.844G>C (p.Glu282Gln)	C1QTNF3-AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
353243	NM_014324.6(AMACR):c.*714T>C	C1QTNF3-AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
501618	NM_014324.6(AMACR):c.109C>A (p.Pro37Thr)	C1QTNF3-AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
501944	NM_014324.6(AMACR):c.1011C>T (p.Ile337=)	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
595442	NM_014324.6(AMACR):c.1083C>T (p.Arg361=)	C1QTNF3-AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
597136	NM_014324.6(AMACR):c.90T>G (p.Arg30=)	C1QTNF3-AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903706	NM_014324.6(AMACR):c.27G>A (p.Val9=)	C1QTNF3-AMACR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1045362	NM_014324.6(AMACR):c.1045C>G (p.His349Asp)	AMACR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1347747	NM_014324.6(AMACR):c.421G>A (p.Glu141Lys)	AMACR	Uncertain significance	criteria provided, single submitter
1354911	NM_014324.6(AMACR):c.514A>G (p.Thr172Ala)	AMACR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1356567	NM_014324.6(AMACR):c.240C>G (p.Phe80Leu)	AMACR	Uncertain significance	criteria provided, single submitter
1374225	NM_014324.6(AMACR):c.254T>C (p.Met85Thr)	AMACR	Uncertain significance	criteria provided, single submitter
1382430	NM_014324.6(AMACR):c.512G>A (p.Arg171His)	AMACR	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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	Definitive	Autosomal recessive	alpha-methylacyl-CoA racemase deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AMACR	Orphanet:79095	Congenital bile acid synthesis defect type 4
PRLR	Orphanet:397685	Familial hyperprolactinemia

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AMACR	HGNC:451	ENSG00000242110	Q9UHK6	Alpha-methylacyl-CoA racemase	gencc,clinvar
TTC23L	HGNC:26355	ENSG00000205838	Q6PF05	Tetratricopeptide repeat protein 23-like	clinvar
C1QTNF3-AMACR	HGNC:49198	ENSG00000273294		C1QTNF3-AMACR readthrough (NMD candidate)	clinvar
PRLR	HGNC:9446	ENSG00000113494	P16471	Prolactin receptor	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.
PRLR	Prolactin receptor	This is a receptor for the anterior pituitary hormone prolactin (PRL).

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · 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
Antibody/Immunoglobulin	1	7.3×	0.390
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

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
TTC23L	Other/Unknown	no		TPR-like_helical_dom_sf, TTC23/TTC23L
C1QTNF3-AMACR	Other/Unknown	no
PRLR	Antibody/Immunoglobulin	yes		Long_hematopoietin_rcpt_CS, FN3_dom, Ig-like_fold

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adult mammalian kidney	1
kidney	1
rectum	1
left testis	1
right testis	1
testis	1
granulocyte	1
stromal cell of endometrium	1
ventricular zone	1
choroid plexus epithelium	1
placenta	1
seminal vesicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AMACR	134	ubiquitous	marker	adult mammalian kidney, rectum, kidney
TTC23L	166	broad	marker	left testis, right testis, testis
C1QTNF3-AMACR	129		yes	ventricular zone, stromal cell of endometrium, granulocyte
PRLR	200	broad	marker	placenta, choroid plexus epithelium, seminal vesicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AMACR	1,602
PRLR	985
TTC23L	354
C1QTNF3-AMACR	0

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRLR	P16471	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AMACR	Q9UHK6	95.79
TTC23L	Q6PF05	84.30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 4 evidence-associated genes (2 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 2 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	571.0×	0.009	AMACR
Synthesis of bile acids and bile salts via 24-hydroxycholesterol	1	439.2×	0.009	AMACR
Prolactin receptor signaling	1	380.7×	0.009	PRLR
Peroxisomal lipid metabolism	1	335.9×	0.009	AMACR
Bile acid and bile salt metabolism	1	248.3×	0.009	AMACR
Growth hormone receptor signaling	1	237.9×	0.009	PRLR
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	228.4×	0.009	AMACR
Synthesis of bile acids and bile salts	1	203.9×	0.009	AMACR
Protein localization	1	95.2×	0.016	AMACR
Peroxisomal protein import	1	86.5×	0.016	AMACR
Metabolism of steroids	1	68.8×	0.018	AMACR
Fatty acid metabolism	1	65.6×	0.018	AMACR
Metabolism of lipids	1	15.8×	0.067	AMACR
Metabolism	1	5.8×	0.165	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
activation of transmembrane receptor protein tyrosine kinase activity	1	1872.4×	0.007	PRLR
activation of Janus kinase activity	1	1404.3×	0.007	PRLR
prostate gland growth	1	702.2×	0.007	PRLR
regulation of epithelial cell differentiation	1	624.1×	0.007	PRLR
cellular response to granulocyte macrophage colony-stimulating factor stimulus	1	432.1×	0.007	PRLR
mammary gland epithelial cell differentiation	1	401.2×	0.007	PRLR
fatty acid beta-oxidation using acyl-CoA oxidase	1	374.5×	0.007	AMACR
bile acid metabolic process	1	330.4×	0.007	AMACR
mammary gland alveolus development	1	330.4×	0.007	PRLR
bile acid biosynthetic process	1	208.1×	0.010	AMACR
steroid biosynthetic process	1	200.6×	0.010	PRLR
lactation	1	140.4×	0.013	PRLR
embryo implantation	1	117.0×	0.014	PRLR
positive regulation of B cell proliferation	1	114.6×	0.014	PRLR
regulation of cell adhesion	1	102.1×	0.014	PRLR
cell surface receptor signaling pathway via JAK-STAT	1	96.8×	0.014	PRLR
response to bacterium	1	64.6×	0.020	PRLR
response to endoplasmic reticulum stress	1	55.6×	0.021	TTC23L
positive regulation of cold-induced thermogenesis	1	54.5×	0.021	PRLR
cytokine-mediated signaling pathway	1	43.5×	0.025	PRLR
negative regulation of apoptotic process	1	11.6×	0.087	PRLR
positive regulation of cell population proliferation	1	11.2×	0.087	PRLR

Therapeutics

Drug target analysis

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

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
AMACR	0	0
TTC23L	0	0
C1QTNF3-AMACR	0	0
PRLR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PRLR	1	Binding: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: 3; 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	1	PRLR
D	Druggable family + AlphaFold only, no drug	1	AMACR
E	Difficult family or no structure, no drug	2	TTC23L, C1QTNF3-AMACR

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AMACR	0	—
TTC23L	0	—
C1QTNF3-AMACR	0	—
PRLR	1	—

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
NCT01668186	Not specified	RECRUITING	Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD)