rs515726176 — CPT2
Rare CPT2 missense variant (p.Arg382Thr) that reduces carnitine palmitoyltransferase II activity, impairing long-chain fatty acid transport into mitochondria and increasing risk of exercise-induced rhabdomyolysis in homozygous carriers.
Details
- Gene
- CPT2
- Chromosome
- 1
- Risk allele
- C
- Clinical
- Uncertain
- Evidence
- Moderate
Population Frequency
Category
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CPT2 Arg382Thr — Rare Variant in Mitochondrial Fatty Acid Transport
The CPT2 gene encodes carnitine palmitoyltransferase II11 carnitine palmitoyltransferase II
an enzyme on the inner mitochondrial membrane that liberates long-chain acylcarnitines back into acyl-CoA form, completing the carnitine shuttle that delivers fatty acids into the mitochondrial matrix for energy production. Without functional CPT2, long-chain fatty acids cannot be burned efficiently — a problem that becomes acute during prolonged exercise, fasting, fever, or cold, when the body depends heavily on fat as its primary fuel.
CPT2 deficiency is the most common inherited disorder of mitochondrial long-chain fatty acid oxidation. The myopathic form — the version most adults carry — typically surfaces in adolescence or early adulthood as episodes of severe muscle pain, weakness, and rhabdomyolysis22 rhabdomyolysis
the rapid breakdown of muscle tissue that releases myoglobin into the bloodstream, potentially causing kidney injury.
The Mechanism
The p.Arg382Thr substitution (Arginine to Threonine at position 382 of the CPT2 protein33 Arginine to Threonine at position 382 of the CPT2 protein) is one of approximately 100 rare private mutations identified in CPT2 deficiency families. Unlike the common p.Ser113Leu variant (found in ~50% of myopathic CPT2 alleles), Arg382Thr has been identified in very few patients and has not been independently characterized biochemically. Like other CPT2 missense variants, it likely reduces the enzyme's structural stability — CPT2 mutants characteristically show abnormal thermodestabilization at 40–45°C44 abnormal thermodestabilization at 40–45°C, which may explain why fever and intense exercise (which raise muscle temperature) preferentially trigger acute episodes.
When CPT2 activity falls below a critical threshold in muscle, long-chain acylcarnitines accumulate in mitochondria, blocking electron transport and disrupting membrane integrity55 blocking electron transport and disrupting membrane integrity. The result is irreversible myocyte damage — detectable as massively elevated creatine kinase (CK) in blood and myoglobinuria.
The Evidence
CPT2 deficiency as a cause of recurrent rhabdomyolysis is well established. Bonnefont et al. (1999)66 Bonnefont et al. (1999) documented over 150 CPT2 myopathic families, and the 2004 comprehensive review confirmed management principles used today. The specific Arg382Thr variant (ClinVar VCV001370451) carries an uncertain significance classification — biophysical modeling predicts 80% probability of functional disruption, but independent clinical evidence for this specific variant is limited to a small number of submitters.
The broader management framework for CPT2 myopathy rests on strong biological rationale and case series. A pilot study of bezafibrate77 pilot study of bezafibrate — a fibrate drug that activates PPARδ and upregulates residual CPT2 activity — showed 39–206% increases in palmitoyl-CoA oxidation across six patients. However, a separate study (Ørngreen et al. 2015, PMID 2533190888 Ørngreen et al. 2015, PMID 25331908) found no benefit, leaving bezafibrate's role uncertain.
Practical Actions
The two most effective interventions are eliminating prolonged fasting and shifting calories toward carbohydrate and medium-chain triglycerides. Carbohydrates provide an alternative fuel that bypasses the CPT2 block entirely; MCT oil (chains of 8–12 carbons) enters mitochondria via a carnitine-independent route. Clinical management guidelines99 Clinical management guidelines recommend MCT oil at 10–45% of daily calories as primary therapy, with triheptanoin (a 7-carbon MCT derivative) preferred where available.
L-carnitine supplementation is reserved for cases where free carnitine falls well below 10 µmol/L — routine supplementation is not recommended and may increase arrhythmia risk in long-chain fatty acid oxidation disorders.
Exercise should be modified rather than eliminated: short-duration, moderate-intensity activity with adequate carbohydrate intake beforehand is generally well tolerated; prolonged fasted exercise is the principal trigger to avoid.
Interactions
Heterozygous carriers of CPT2 variants rarely develop rhabdomyolysis under ordinary conditions, but a second CPT2 mutation on the opposite allele (compound heterozygosity) produces the same functional deficiency as homozygosity. Any user carrying rs515726176 (p.Arg382Thr) and a second pathogenic CPT2 variant — such as the common p.Ser113Leu (rs74315294) — should be considered functionally affected regardless of homozygous status at either individual site.
Nutrient Interactions
Genotype Interpretations
What each possible genotype means for this variant:
No CPT2 Arg382Thr variant detected
You carry two copies of the reference allele at this position in the CPT2 gene, meaning you do not carry the rare Arg382Thr missense variant. This site does not contribute to CPT2 deficiency risk. The Arg382Thr allele is found in fewer than 1 in 100,000 people globally, making non-carrier status by far the most common result.
One copy of the rare CPT2 Arg382Thr variant
CPT2 deficiency follows autosomal recessive inheritance: two pathogenic copies are required for the classical myopathic syndrome. As a single-copy carrier, your overall risk is low, but it is clinically relevant for two reasons: (1) each child with a CPT2-carrier partner has a 25% chance of being affected; and (2) rare reports document heterozygous individuals with mild exercise-induced symptoms, though this is not the expected pattern.
The Arg382Thr variant at ClinVar VCV001370451 is classified as uncertain significance, meaning that while biophysical modeling suggests functional disruption (~80% probability), direct clinical evidence is limited. Monitoring CK during illness or extreme exertion is reasonable for anyone with heterozygous CPT2 variants and personal or family history of unexplained rhabdomyolysis.
Two copies of the CPT2 Arg382Thr variant — high risk for CPT2 deficiency
CPT2 deficiency (OMIM #255110) impairs the mitochondrial carnitine shuttle, preventing long-chain fatty acids from reaching the enzymes that burn them for energy. In the myopathic form, the enzyme retains some residual activity at rest but becomes critically insufficient when metabolic demand rises — particularly during prolonged exercise (especially when fasted), febrile illness, or exposure to cold. Male sex predominates 2:1 among affected individuals.
Acute episodes are medical emergencies: rhabdomyolysis releases myoglobin that can precipitate acute kidney injury requiring dialysis. Between episodes, most individuals are entirely asymptomatic — which delays diagnosis for years.
The Arg382Thr variant carries an uncertain significance classification in ClinVar because it has not been reported independently in enough patients to meet pathogenic criteria. However, biophysical modeling assigns ~80% probability of functional disruption, and the clinical picture of CPT2 deficiency from any confirmed biallelic CPT2 missense variant is well-characterized and actionable. Seek formal confirmation through enzyme activity testing (muscle or fibroblasts) and acylcarnitine profiling (elevated C16, C18:1 acylcarnitines are the biochemical hallmark).