AMACR

Chr 5AR

alpha-methylacyl-CoA racemase

Also known as: AMACRD, CBAS4, P504S, RACE, RM

NCBI Gene: 23600 ENSG00000242110 UniProt: Q9UHK6 OMIM: 604489

The protein is a racemase that catalyzes the interconversion of (R)- and (S)-stereoisomers of alpha-methyl-branched-chain fatty acyl-CoA esters, including pristanoyl-CoA and bile acid intermediates, which is necessary for their degradation by peroxisomal beta-oxidation. Mutations cause autosomal recessive alpha-methylacyl-CoA racemase deficiency, presenting with adult-onset sensorimotor neuropathy, pigmentary retinopathy, and adrenomyeloneuropathy due to defects in bile acid synthesis. The gene shows moderate tolerance to loss-of-function variation (LOEUF 0.747).

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.752 OMIM phenotypes

Clinical Summary— AMACR

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Gene-Disease Validity (ClinGen)

alpha-methylacyl-CoA racemase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 245 VUS of 461 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — AMACR

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.75LOEUF

pLI 0.027

Z-score 2.24

OE 0.36 (0.18–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.56Z-score

OE missense 0.90 (0.80–1.01)

207 obs / 230.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.18–0.75)

0≤0.351.4

Missense OE?0.90 (0.80–1.01)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 5 / 14.1Missense obs/exp: 207 / 230.8Syn Z: 1.17

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveAMACR-related alpha-methylacyl-CoA racemase deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7036th %ile

GOF

0.5954th %ile

LOF

0.2680th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

461 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic3

VUS245

Likely Benign165

Benign22

Conflicting23

Pathogenic

Likely Pathogenic

245

VUS

165

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	1	0	2
Likely Pathogenic	2	1	0	0	3
VUS	15	193	36	1	245
Likely Benign	2	19	67	77	165
Benign	0	8	14	0	22
Conflicting	—				23
Total	19	222	118	78	460

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

25 pathogenic / likely-pathogenic (of 42) ClinVar copy-number / structural variants overlap AMACR — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →