rs1052373 — MYBPC3

The Endurance Athlete's Genetic Edge

Elite endurance athletes—those competing in marathons, cycling road races, cross-country skiing, and football matches requiring sustained high-intensity output for 90+ minutes—often share a common genetic signature. Among the most significant is rs1052373 in the MYBPC3 gene, which encodes cardiac myosin-binding protein C¹¹ cardiac myosin-binding protein C
a regulatory protein that fine-tunes the force and speed of heart muscle contraction. A landmark genome-wide association study²² landmark genome-wide association study
Ahmetov et al. 2020. Meta-analysis of 1,206 elite European, Russian, and Japanese athletes found that individuals with the GG genotype were 2.2 times more likely to become elite endurance athletes compared to those with AA or AG genotypes (P = 1.43 × 10⁻⁸). Among Russian elite athletes, GG homozygotes showed significantly higher VO₂max—the gold-standard measure of aerobic capacity—than AG or AA carriers (P = 0.005).

The Mechanism

Though rs1052373 is a synonymous variant³³ synonymous variant
it doesn't change the amino acid sequence of the protein—substituting one glutamic acid codon (GAG) for another (GAA) at position 1096—it appears to influence gene expression or splicing efficiency in ways that enhance cardiac adaptation to endurance training. MYBPC3 normally acts as a molecular brake on cardiac contraction: when phosphorylated during exercise, it releases myosin heads from their "super-relaxed" state, allowing them to bind actin and generate force. The G allele may subtly modulate this regulatory balance, enabling more efficient oxygen delivery during sustained high-output performance.

MYBPC3 deficiency studies⁴⁴ MYBPC3 deficiency studies
Mamidi et al. 2022. Shows MYBPC3 loss activates NF-κB pathway, reduces inflammation, and shifts metabolism toward fatty acid oxidation have revealed that partial loss of cMyBP-C function reduces cardiac inflammation and enhances fatty acid oxidation—a more efficient fuel source during prolonged exercise. This metabolic shift may explain why GG carriers show superior endurance capacity: their hearts can sustain high cardiac output longer without depleting glycogen stores or accumulating lactate.

The Evidence

The initial discovery came from a GWAS⁵⁵ discovery came from a GWAS
Miyamoto-Mikami et al. 2020. Analyzed 476,728 SNPs in 796 European elite athletes, replicated in Russian and Japanese cohorts comparing athletes in high-aerobic sports (marathon, cycling, cross-country skiing) versus low/moderate-aerobic sports (sprinting, jumping, throwing). The rs1052373 GG genotype emerged as the strongest genome-wide significant hit. Validation in independent cohorts from Russia (n=410) and Japan (n=466) confirmed the association, with the combined meta-analysis yielding an odds ratio of 2.17 (95% CI: 1.67–2.84).

A 2023 follow-up metabolomics study⁶⁶ 2023 follow-up metabolomics study
Li et al. 2023. Metabolite profiling in 120 elite Chinese athletes linked the G allele to elevated levels of androstenediol (3β,17β) disulfate (P = 1.82 × 10⁻⁵), a testosterone precursor involved in steroid metabolism. This suggests the variant influences both cardiac contractility and hormonal pathways supporting muscle recovery and adaptation. Four metabolites—quinate, theophylline, decanoylcarnitine, and ursodeoxycholic acid—were also associated with MYBPC3 expression and endurance phenotypes, though their causal roles remain under investigation.

A 2023 comprehensive review⁷⁷ A 2023 comprehensive review
Pickering & Kiely. Listed rs1052373 G among the seven most promising genetic markers for endurance athlete status, alongside PPARGC1A rs8192678 (mitochondrial biogenesis) and AMPD1 rs17602729 (purine metabolism). Importantly, the rs1052373 association held across multiple ethnic populations, suggesting a fundamental rather than population-specific effect.

Practical Actions

If you carry one or two G alleles, you possess a genetic advantage for endurance performance. Your heart is likely more efficient at sustaining high cardiac output during prolonged exercise, and your metabolic profile may favor fat oxidation over glycogen depletion. This doesn't guarantee elite status—training, nutrition, psychology, and opportunity all matter—but it does suggest your physiology is well-suited to endurance disciplines.

Training optimization: The GG genotype responds especially well to high-intensity interval training⁸⁸ high-intensity interval training
4×4 min at 90-95% HRmax with 3 min active recovery improves VO₂max more than steady-state training. Prioritize intervals of 3–5 minutes at near-maximal aerobic speed, which have been shown to produce the largest VO₂max gains. Your genetic advantage is maximized when you push your heart's upper limits.

Monitoring cardiac adaptation: Use heart rate variability (HRV)⁹⁹ heart rate variability (HRV)
parasympathetic-mediated recovery indicator to track training adaptation. Endurance athletes typically show higher resting HRV and faster heart rate recovery. When HRV drops outside your weekly baseline, scale back intensity to avoid overtraining—your cardiac system may be reaching its adaptive ceiling despite your genetic edge.

Fuel strategy: The G allele's association with enhanced fatty acid oxidation suggests you may benefit from periodized carbohydrate intake—training fasted or low-carb to upregulate fat-burning enzymes, then fueling with carbs for competition. However, this remains speculative; no studies have directly tested nutrition interventions based on MYBPC3 genotype.

Interactions

The endurance phenotype is polygenic—no single SNP determines performance. rs1052373 works synergistically with other endurance-associated variants including PPARGC1A rs8192678¹⁰¹⁰ PPARGC1A rs8192678
enhances mitochondrial biogenesis and oxidative capacity, ACTN3 rs1815739¹¹¹¹ ACTN3 rs1815739
XX genotype (absence of alpha-actinin-3 fast-twitch protein) associated with endurance over power, and PPARA rs4253778¹²¹² PPARA rs4253778
regulates fatty acid oxidation pathways. If you carry beneficial alleles at multiple loci, the cumulative effect may be substantial.

Conversely, the MYBPC3 gene is also implicated in hypertrophic cardiomyopathy¹³¹³ hypertrophic cardiomyopathy
pathogenic truncating mutations cause HCM, a disease characterized by abnormal thickening of the heart muscle. rs1052373 itself is classified as benign¹⁴¹⁴ classified as benign
all six ClinVar submissions rate it benign for HCM, but it raises an interesting paradox: variants in the same gene can cause both pathological hypertrophy (disease) and adaptive hypertrophy (athlete's heart). The distinction lies in whether the heart thickens symmetrically with preserved function (adaptive) or asymmetrically with impaired relaxation (pathological). If you have a family history of HCM, genetic counseling is warranted regardless of your rs1052373 status.