AMACR

Chr 5AR

alpha-methylacyl-CoA racemase

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

NCBI Gene: 23600 ENSG00000242110 UniProt: Q9UHK6

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]

Primary Disease Associations & Inheritance

Alpha-methylacyl-CoA racemase deficiencyMIM #614307

Bile acid synthesis defect, congenital, 4MIM #214950

UniProtCongenital bile acid synthesis defect 4

500

ClinVar variants

Pathogenic / LP

0.03

pLI score

Active trials

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

30 Pathogenic / Likely Pathogenic· 258 VUS of 500 total submissions

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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.75LOEUF

pLI 0.027

Z-score 2.24

OE 0.36 (0.18–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.56Z-score

OE missense 0.90 (0.80–1.01)

207 obs / 230.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.36 (0.18–0.75)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.90 (0.80–1.01)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.84

0≤1.21.6

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