AMACR

protein-coding

alpha-methylacyl-CoA racemase

Gene summary

This gene encodes a racemase. The encoded enzyme interconverts pristanoyl-CoA and C27-bile acylCoAs between their (R)- and (S)-stereoisomers. The conversion to the (S)-stereoisomers is necessary for degradation of these substrates by peroxisomal beta-oxidation. Encoded proteins from this locus localize to both mitochondria and peroxisomes. Mutations in this gene may be associated with adult-onset sensorimotor neuropathy, pigmentary retinopathy, and adrenomyeloneuropathy due to defects in bile acid synthesis. Alternatively spliced transcript variants have been described. Read-through transcription also exists between this gene and the upstream neighboring C1QTNF3 (C1q and tumor necrosis factor related protein 3) gene. [provided by RefSeq, Mar 2011]

MANE transcript

NM_014324.6

Inheritance

ClinVar variants

P:6U:211B:124

Top phenotype

Bile acid synthesis defect, congenital, 4; Alpha-methylacyl-CoA racemase deficiency

gnomAD constraint

pLI —, LoF o/e 0.36

Max pathogenic AF

—

Genomic locus

chr5:33,986,165-34,008,104

External References & Databases

Ensembl (ENSG00000242110)

Transcript & Mutation Effects

hg38 • Region Span ~21.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

alpha-methylacyl-CoA racemase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013681

Submitter: Labcorp Genetics (formerly Invitae)

alpha-methylacyl-CoA racemase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013681

Submitter: PanelApp Australia

alpha-methylacyl-CoA racemase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013681

Submitter: G2P

alpha-methylacyl-CoA racemase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013681

Submitter: ClinGen

The relationship between *AMACR* and alpha-methylacyl-CoA racemase (AMACR) deficiency (congenital bile acid synthesis defect type 4 included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of September, 2019 and updated as of March 2022. AMACR encodes an enzyme that interconverts pristanoyl-CoA and C27-bile acylCoAs between their (R)- and (S)-stereoisomers. The conversion to the (S)-stereoisomers is necessary for degradation of these substrates by peroxisomal beta-oxidation. Patients with *AMACR* variants present typically with neuropathy and retinitis pigmentosa, with elevated pristanic acid levels. *AMACR* was first reported in relation to autosomal recessive AMACR deficiency in 2000 (Ferdinandusse et al, PMID: 10655068). Summary of Case Level Data (12 points): At least 11 patients across 8 publications have been reported with the same homozygous missense variant, Ser52Pro (PMIDs: 10655068, 12512044, 21686617, 21576695, 20821052, 15249642, 33047465, 39313810). A few other missense variants have also been reported (PMID: 10655068, 20921516, 23286897, 34267495). A deletion encompassing 5 genes on 5p13.3 including AMACR is reported in three patients (2 siblings) with AMACR deficiency (PMID: 22987308, 39313810). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. Summary of experimental data (2 points): This gene-disease association is supported by a mouse model that recapitulates the human biochemical phenotype (PMID 25168382). The enzyme is highly expressed in peroxisomes, followed by mitochondria (PMID: 7649182). In summary, this gene-disease relationship of *AMACR* and AMACR deficiency In summary, there is definitive evidence to support the relationship between *AMACR* and autosomal recessive AMACR deficiency. This gene-disease pair was originally evaluated by the Peroxisomal Disorders GCEP Mar 31, 2022. It was reevaluated on 11/22/2025. As a result of this reevaluation, the classification changed from Moderate to Definitive based on additional publications since the last evaluation (PMID: 39313810, 31951345, 35428665, 39544692, 39132899, 38166212, 40643170).

congenital bile acid synthesis defect 4SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008967

Submitter: Orphanet

alpha-methylacyl-CoA racemase deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013681

Submitter: Ambry Genetics

congenital bile acid synthesis defect 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008967

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Bile acid synthesis defect, congenital, 4; Alpha-methylacyl-CoA racemase deficiencyAR

Manifestation: Biochemical; Endocrine; Gastrointestinal; Hematologic; Neurologic; Ophthalmologic

Intervention: Biochemical; Gastrointestinal; Hematologic

Rationale: Individuals with Bile acid synthesis defect, congenital, 4 may present with manifestations of hepatic disease, and medical therapy (eg, with oral cholic acid, and Vitamin K for bleeding) has been reported as beneficial; In Alpha-methylacyl-CoA Racemase deficiency, early diagnosis may allow potentially benefical dietary/medical therapy (eg, restriction of dietary phytanic acid and pristanic acid)

Refs: 9584266; 10655068; 11473573; 12512044; 15249642; 18032455; 20821052; 21576695; 23286897

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AMACR variants in ClinVar

9 Conditions Cataloged

Alpha-methylacyl-CoA racemase deficiencyTotal: 337

not providedTotal: 83

Inborn genetic diseasesTotal: 71

AMACR-related disorderTotal: 61

not specifiedTotal: 43

Congenital bile acid synthesis defect 4Total: 10

Mitochondrial complex I deficiencyTotal: 1

Autosomal recessive AMACR-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014324.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	114 clinvar		115
missense		3 clinvar	194 clinvar	8 clinvar	2 clinvar	207
nonsense			5 clinvar			5
start loss			1 clinvar			1
frameshift		2 clinvar	7 clinvar			9
splice donor/acceptor (+/-2bp)		1 clinvar	3 clinvar			4
Total	0	6	211	122	2	341

Highest pathogenic variant AF is 0.0008360667

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014324.6	RefSeq	NP_055139.4	5	MANE Select
ENST00000335606.11	Ensembl	ENSP00000334424.6	5	MANE Select
NM_001167595.2	RefSeq	NP_001161067.1	6	Standard
NM_203382.3	RefSeq	NP_976316.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Peroxisome - Homo sapiens (human)
Primary bile acid biosynthesis - Homo sapiens (human)
Ibuprofen Pathway, Pharmacokinetics
27-Hydroxylase Deficiency
Bile Acid Biosynthesis

Biological Process

protein targeting to peroxisome
bile acid biosynthetic process
bile acid metabolic process
fatty acid beta-oxidation using acyl-CoA oxidase

Molecular Function

signaling receptor binding
alpha-methylacyl-CoA racemase activity

Cellular Component

cytoplasm
mitochondrion
peroxisome
peroxisomal matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000382085
Coding exons: 6
Length: 21938
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125748
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.557	207	231	0.897	0.0000121	2539
Missense (PolyPhen)		66	73.939	0.89263		820
Synonymous	1.17	75	89.1	0.842	0.00000485	791
Loss of Function	2.24	5	14.1	0.355	6.59e-7	173

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Racemization of 2-methyl-branched fatty acid CoA esters. Responsible for the conversion of pristanoyl-CoA and C27-bile acyl-CoAs to their (S)-stereoisomers.;
Disease: DISEASE: Alpha-methylacyl-CoA racemase deficiency (AMACRD) [MIM:614307]: A rare autosomal recessive peroxisomal disorder characterized by elevated plasma concentrations of pristanic acid C27-bile-acid intermediates, and adult onset of variable neurodegenerative symptoms affecting the central and peripheral nervous systems. Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities on brain imaging. {ECO:0000269|PubMed:10655068}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Congenital bile acid synthesis defect 4 (CBAS4) [MIM:214950]: A disorder characterized by the presence of trihydroxycoprostanic acid in the bile and absence of cholic acid. Patients manifest neonatal jaundice, intrahepatic cholestasis and bile duct deficiency. {ECO:0000269|PubMed:10655068, ECO:0000269|PubMed:12512044}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.314

Intolerance Scores

LoFtool: 0.661
RVIS EVS: 1.42
RVIS percentile EVS: 94.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.315

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	High	Medium	High
Cancer	High	Medium	High