rs6746030 — SCN9A R1150W

The Nav1.7 Pain Sensitivity Variant — How Your Sodium Channels Set Your Pain Threshold

The SCN9A gene encodes Nav1.7¹¹ Nav1.7
a voltage-gated sodium channel critical for transmitting pain signals from peripheral nerves to the brain. This channel acts as a molecular amplifier in nociceptors—specialized sensory neurons that detect potentially harmful stimuli. The rs6746030 variant causes an amino acid substitution from arginine to tryptophan at position 1150 (R1150W), located in the intracellular loop between domains II and III of the channel protein.

While rare mutations in SCN9A cause dramatic pain disorders—complete insensitivity to pain when the channel is nonfunctional, or severe episodic pain syndromes like erythromelalgia when overactive²² complete insensitivity to pain when the channel is nonfunctional, or severe episodic pain syndromes like erythromelalgia when overactive—the common rs6746030 variant has a more subtle but measurable effect. The A allele occurs at approximately 10-13% frequency globally and increases pain sensitivity quantitatively rather than causing a discrete pain disorder.

The Mechanism

The R1150W substitution replaces a positively charged arginine with a non-polar tryptophan in a functionally critical region of Nav1.7. Electrophysiological studies using patch-clamp recordings show that the A allele alters voltage-dependent slow inactivation of the channel (p=0.042)³³ Electrophysiological studies using patch-clamp recordings show that the A allele alters voltage-dependent slow inactivation of the channel (p=0.042), causing the channel to remain active longer than normal. This increased activity means that small, sub-threshold stimuli are more likely to be amplified into full action potentials, effectively lowering the threshold at which pain signals are generated and transmitted.

The arginine at position 1150 is evolutionarily conserved across species⁴⁴ evolutionarily conserved across species, suggesting functional importance. The variant's effect is mediated specifically through C-fiber activation—the thin, unmyelinated nerve fibers that transmit slow, burning pain and temperature sensation.

The Evidence

The association between rs6746030 and pain perception has been replicated across multiple clinical populations and experimental settings. The landmark 2010 study by Reimann et al. genotyped 27 SNPs in SCN9A across 578 individuals with osteoarthritis and found rs6746030 showed the strongest association with pain scores (p=0.016)⁵⁵ The landmark 2010 study by Reimann et al. genotyped 27 SNPs in SCN9A across 578 individuals with osteoarthritis and found rs6746030 showed the strongest association with pain scores (p=0.016). This finding was then replicated in four additional cohorts: 195 people with sciatica, 100 amputees with phantom limb pain, 179 individuals after lumbar disc surgery, and 205 people with pancreatitis. Across all five cohorts totaling 1,277 individuals, the combined p-value was 0.0001, with A allele carriers consistently reporting more pain⁶⁶ Across all five cohorts totaling 1,277 individuals, the combined p-value was 0.0001, with A allele carriers consistently reporting more pain.

In patients with chronic disc herniation, A allele carriers reported significantly higher preoperative back pain intensity (VAS 7.5 ± 2.4) compared to GG homozygotes (VAS 6.5 ± 2.7, p=0.012)⁷⁷ In patients with chronic disc herniation, A allele carriers reported significantly higher preoperative back pain intensity (VAS 7.5 ± 2.4) compared to GG homozygotes (VAS 6.5 ± 2.7, p=0.012). The effect was similar for leg pain (VAS 7.8 vs 6.8, p=0.013). A study of 309 healthy Chinese women found the A allele associated with increased sensitivity to mechanical pain thresholds⁸⁸ A study of 309 healthy Chinese women found the A allele associated with increased sensitivity to mechanical pain thresholds.

In 214 combat athletes and 92 controls, carriers of the GA and AA genotypes showed decreased pain tolerance compared to GG homozygotes⁹⁹ In 214 combat athletes and 92 controls, carriers of the GA and AA genotypes showed decreased pain tolerance compared to GG homozygotes. Interestingly, training appeared to partially override genetic predisposition—combat athletes showed higher pain thresholds than controls regardless of genotype, suggesting pain tolerance is modifiable through conditioning.

A 2016 study in cancer patients receiving oxaliplatin chemotherapy found an unexpected protective effect: the A allele was associated with lower risk of severe neuropathy (OR=0.39, 95% CI 0.16-0.96, p=0.041)¹⁰¹⁰ A 2016 study in cancer patients receiving oxaliplatin chemotherapy found an unexpected protective effect: the A allele was associated with lower risk of severe neuropathy (OR=0.39, 95% CI 0.16-0.96, p=0.041). This counterintuitive finding suggests the variant's effect may be context-dependent or pathway-specific.

Not all studies have found associations. A 2012 meta-analysis of four population-based cohorts totaling 1,071 chronic widespread pain cases and 3,212 controls found no association (OR=0.96, p=0.567)¹¹¹¹ A 2012 meta-analysis of four population-based cohorts totaling 1,071 chronic widespread pain cases and 3,212 controls found no association (OR=0.96, p=0.567). A recent 2025 UK Biobank analysis of over 148,000 carriers found no increased risk of chronic pain, neuropathic pain, or opioid prescriptions¹²¹² A recent 2025 UK Biobank analysis of over 148,000 carriers found no increased risk of chronic pain, neuropathic pain, or opioid prescriptions, suggesting the variant's effect may be limited to acute or stimulus-evoked pain rather than chronic pain conditions.

Practical Implications

If you carry one or two copies of the A allele, you may experience pain more intensely than others given the same stimulus. This doesn't mean you're fragile or overreacting—it reflects a measurable difference in how your nociceptors process signals. The effect is modest (typically a 0.5-1 point difference on a 10-point pain scale) but consistent across diverse pain contexts.

This genetic insight may be particularly relevant for surgical planning, pain management strategies, and anesthesia requirements. The variant has been associated with altered response to propofol anesthesia, with A allele carriers showing lower bispectral index values after induction¹³¹³ The variant has been associated with altered response to propofol anesthesia, with A allele carriers showing lower bispectral index values after induction, suggesting greater anesthetic susceptibility. For post-operative pain management, proactive rather than reactive approaches may be warranted.

Physical training appears to partially override genetic predisposition, as combat athletes with pain-sensitive genotypes still developed higher pain thresholds than untrained controls. This suggests that regular exposure to controlled painful stimuli can build tolerance through neuroplastic adaptation, a phenomenon known as the repeated bout effect.

Interactions

SCN9A variants may interact with other pain pathway genes including COMT (catechol-O-methyltransferase, which affects pain modulation through dopamine and norepinephrine metabolism) and GCH1 (GTP cyclohydrolase 1, involved in synthesis of tetrahydrobiopterin, a cofactor for neurotransmitter production). Individuals carrying pain-sensitizing variants in multiple genes may experience additive effects on pain perception.

The variant has shown gene-gene interactions with GABAA receptor SNPs in determining propofol anesthesia susceptibility¹⁴¹⁴ The variant has shown gene-gene interactions with GABAA receptor SNPs in determining propofol anesthesia susceptibility, suggesting combined effects on neuronal excitability beyond pain pathways alone.