rs2010963 — VEGFA G-634C (+405G>C)

VEGFA G-634C — The Angiogenesis Adapter

The VEGFA gene encodes vascular endothelial growth factor A¹¹ vascular endothelial growth factor A
The master regulator of angiogenesis (new blood vessel formation), critical for oxygen delivery to tissues, the master regulator of angiogenesis — the formation of new blood vessels. This promoter variant, located at position -634 in the gene's regulatory region, directly affects how much VEGF-A your cells produce. The C allele increases VEGF-A expression, leading to higher circulating levels and greater angiogenic potential. The G allele results in lower baseline VEGF production.

This SNP is one of only three genetic variants with replicated findings²² replicated findings
Among 99 unique polymorphisms studied in football players, only ACTN3 R577X, ACAN rs1516797, and VEGFA rs2010963 showed consistent associations across independent cohorts across independent cohorts of professional football players — making it among the most robust findings in sports genetics. But its implications extend far beyond athletics: VEGF levels influence wound healing, cardiovascular health, exercise adaptation, and soft tissue injury susceptibility.

The Mechanism

The -634G>C polymorphism sits in the 5′-untranslated region of the VEGFA gene, a regulatory region that controls gene expression³³ gene expression
Transcription rates determine how much protein gets made from a gene. The C allele enhances promoter activity, resulting in higher VEGFA mRNA levels and increased protein production. Functional studies⁴⁴ Functional studies
Vailati et al. 2012 — analysis of 53 human retinal samples show that C-allele carriers (CC or CG genotypes) have significantly higher VEGFA gene expression than GG individuals (5.15 and 3.72 arbitrary units vs 2.62, P=0.045).

VEGF-A is the central angiogenic factor in skeletal muscle. During exercise, muscle contraction triggers VEGF release into the muscle interstitium⁵⁵ muscle interstitium
The fluid-filled space between muscle fibers and capillaries, where it binds to VEGF receptors on capillary endothelial cells. This stimulates two forms of capillary growth: sprouting angiogenesis⁶⁶ sprouting angiogenesis
New capillaries bud from existing vessels through endothelial cell proliferation and basement membrane remodeling (driven by VEGF signaling) and longitudinal splitting⁷⁷ longitudinal splitting
A capillary lumen splits into two parallel vessels through mechanical stretching of endothelial cells (driven by shear stress and nitric oxide). Higher baseline VEGF production in C-allele carriers means a stronger angiogenic response to training stimuli.

But VEGF also upregulates matrix metalloproteinases⁸⁸ matrix metalloproteinases
MMPs — enzymes that degrade extracellular matrix proteins including collagen (MMPs), which are necessary for capillary growth but also weaken the extracellular matrix (ECM). Since more than 80% of muscle force⁹⁹ more than 80% of muscle force
Force transmission research shows lateral force transfer to ECM is critical for strength is transmitted laterally to the ECM rather than along the muscle fiber, excessive MMP activity may impair force transmission. This explains why GG individuals — with lower VEGF and thus lower MMP activity — show superior strength gains from resistance training.

The Evidence

The most rigorous evidence comes from a within-subject crossover study¹⁰¹⁰ within-subject crossover study
Pickering et al. 2023 — 30 healthy men completed both resistance and endurance training in random order where 30 healthy men completed both resistance training (4 weeks of knee extensions at 80% 1-RM) and endurance training (4 weeks of cycling at 70-90% max heart rate), separated by a 3-week washout. VEGFA rs2010963 GG homozygotes increased maximum strength by +20.9% after resistance training but only +8.4% in VO₂peak after endurance training (P=0.005). In contrast, C-allele carriers gained only +12.2% strength — significantly less than GG individuals (P=0.04) — though their endurance improvements were comparable.

The authors propose that lower VEGF in GG individuals preserves ECM integrity during resistance training, allowing more effective lateral force transmission and greater hypertrophy. C-allele carriers' higher VEGF drives angiogenesis but also MMP-mediated ECM degradation, blunting their strength response.

For injury risk, the evidence is equally compelling. A meta-analysis¹¹¹¹ meta-analysis
Zhang et al. 2024 — systematic review of 4 studies with 1,061 cases and 986 controls of tendon and ligament injuries found that in European populations, the CC genotype conferred OR 1.40 (95% CI 1.00-1.94, P=0.049) for injury risk compared to GG. The C allele itself showed OR 1.15 (95% CI 1.00-1.32, P=0.045), with the G allele demonstrating protective effects. Specifically, rs2010963 CC¹²¹² rs2010963 CC
Systematic review of genetic predisposition to injury in football homozygotes had greater risk of ACL and ligament/tendon injury than G-allele carriers, replicated across two independent football cohorts.

The mechanism is likely tied to VEGF's role in tissue healing¹³¹³ tissue healing
VEGF is highly expressed 2-3 weeks post-ACL surgery and critical for graft remodeling. While adequate angiogenesis is necessary for tendon repair, excessive VEGF upregulates MMPs that degrade collagen, weakening connective tissue structure. CC individuals' chronically higher VEGF may predispose to tendon/ligament fragility under load.

Training Adaptations

The GG genotype confers a clear advantage for resistance training. The +20.9% strength gain in GG individuals versus +12.2% in C-allele carriers represents a 71% greater adaptation to the same training stimulus. This is among the largest effect sizes for any single SNP in exercise genetics.

For endurance training, the picture is more nuanced. C-allele carriers have higher circulating VEGF and greater angiogenic potential, which theoretically should enhance capillary density and oxygen delivery. Some studies report better aerobic capacity¹⁴¹⁴ better aerobic capacity
C allele associated with higher VO₂max values in some cohorts in C-allele carriers. However, the crossover study found no significant difference in VO₂peak gains between genotypes (+8-9% for both). This may reflect that angiogenesis, while important, is just one of many adaptations to endurance training (mitochondrial biogenesis, fiber-type shifts, etc.).

Injury Prevention

For C-allele carriers — particularly CC homozygotes — soft tissue injury risk is elevated. This is especially relevant for athletes in high-stress sports (football, basketball, skiing) where ACL and tendon injuries are common. The OR 1.40 for CC versus GG translates to roughly 40% higher odds of injury per exposure event, though absolute risk depends on sport, training load, and biomechanics.

Interactions

VEGFA rs2010963 is part of a functional haplotype with two other promoter SNPs: rs699947¹⁵¹⁵ rs699947
-2578C/A polymorphism in VEGFA promoter (-2578C/A) and rs1570360¹⁶¹⁶ rs1570360
-1154G/A polymorphism in VEGFA promoter (-1154G/A). The A-G-G haplotype (rs699947-rs1570360-rs2010963) has been associated with increased risk of chronic Achilles tendon injury. Individuals carrying multiple high-VEGF alleles across these SNPs may have compounded angiogenic drive and correspondingly greater MMP activity.

The interplay with nitric oxide¹⁷¹⁷ nitric oxide
NO is produced by endothelial NOS in response to shear stress and by neuronal NOS during muscle contraction (NO) is also critical. NO and VEGF work synergistically: VEGF upregulates endothelial NOS (eNOS), and NO in turn enhances VEGF receptor sensitivity. Genetic variants affecting NO production (e.g., NOS3¹⁸¹⁸ NOS3
Endothelial nitric oxide synthase gene polymorphisms polymorphisms) may modulate the phenotypic effects of VEGFA rs2010963.