rs1805007 — MC1R R151C

The Redhead Gene: More Than Just Hair Color

The MC1R gene encodes the melanocortin-1 receptor, a protein on the surface of melanocytes that controls pigmentation. When functioning normally, MC1R activation stimulates production of eumelanin¹¹ eumelanin
dark brown/black pigment that provides UV protection. The R151C variant (rs1805007) — where arginine at position 151 is replaced by cysteine — renders the receptor completely nonfunctional²² renders the receptor completely nonfunctional
Frändberg et al. showed this variant cannot stimulate cyclic AMP production despite binding alpha-MSH with normal affinity, shifting melanin synthesis toward pheomelanin³³ pheomelanin
red/yellow pigment associated with fair skin and red hair.

But the effects extend far beyond pigmentation. This loss of MC1R function has profound implications for pain processing and anesthesia response, making R151C one of the most clinically relevant genetic variants in perioperative medicine.

The Mechanism

The R151C substitution creates a loss-of-function receptor that behaves as a recessive mutation⁴⁴ behaves as a recessive mutation
heterozygotes with one functional copy have intermediate pigmentation; two copies are needed for the full red hair phenotype. At the molecular level, the variant protein binds alpha-melanocyte-stimulating hormone (α-MSH) normally but fails to activate downstream cAMP signaling. This disruption affects not only melanocytes but also MC1R expression in other tissues including the periaqueductal gray — a brain region central to pain modulation.

The impaired receptor function increases production of pheomelanin, which may contribute to melanomagenesis through UV-independent oxidative damage⁵⁵ may contribute to melanomagenesis through UV-independent oxidative damage
pheomelanin generates reactive oxygen species under UV exposure. Additionally, MC1R variants appear to influence pain pathways independently of their pigmentation effects, possibly through altered melanocortin signaling in the central nervous system.

The Evidence

Anesthesia requirement: In a landmark 2004 study, Liem et al. demonstrated that redheads required 19% more desflurane anesthesia⁶⁶ Liem et al. demonstrated that redheads required 19% more desflurane anesthesia
study of 20 women (10 redheads with MC1R variants including R151C, 10 dark-haired controls) showed highly significant difference P=0.0004 to prevent movement in response to electrical pain stimulation compared to dark-haired controls. The finding was highly statistically significant (P=0.0004) and consistent with longstanding anecdotal observations from anesthesiologists⁷⁷ consistent with longstanding anecdotal observations from anesthesiologists
clinicians have long reported needing more anesthesia for redheaded patients.

Pain sensitivity: The relationship between R151C and pain is complex and sex-specific. Mogil et al. found that women with two variant MC1R alleles displayed significantly greater analgesia from kappa-opioid pentazocine⁸⁸ Mogil et al. found that women with two variant MC1R alleles displayed significantly greater analgesia from kappa-opioid pentazocine
study of 24 redheads and 24 controls; 5 women homozygous or compound heterozygous for MC1R variants showed markedly increased response than all other groups — an effect not seen in men or heterozygotes. However, redheads show reduced responsiveness to subcutaneous lidocaine and increased thermal pain sensitivity⁹⁹ reduced responsiveness to subcutaneous lidocaine and increased thermal pain sensitivity
Liem et al. 2005 showed redheaded women required more lidocaine for effective anesthesia.

Melanoma and skin cancer risk: The R151C variant substantially increases melanoma risk¹⁰¹⁰ substantially increases melanoma risk
pooled analysis from M-SKIP project showed carriers of R151C had significantly elevated melanoma risk, particularly in darker-pigmented individuals, with effects both dependent on and independent of the fair skin phenotype. A Dutch study found R151C overrepresented in melanoma patients with p16-Leiden mutations¹¹¹¹ Dutch study found R151C overrepresented in melanoma patients with p16-Leiden mutations
R151C contributed increased melanoma risk even after correcting for its effect on skin type, suggesting involvement in melanoma tumorigenesis through multiple pathways. For non-melanoma skin cancers, carriers face a 2- to 3-fold increased risk¹²¹² carriers face a 2- to 3-fold increased risk
meta-analysis showed R151C had highest attributable risk for both basal cell and squamous cell carcinoma.

Red hair genetics: In a genome-wide association study of nearly 7,000 Icelanders and Dutch individuals¹³¹³ genome-wide association study of nearly 7,000 Icelanders and Dutch individuals
Sulem et al. 2007, discovery sample 2,986 Icelanders plus replication samples, the T allele of R151C showed extraordinary association with red hair (OR=12.47, P=2.0×10⁻¹⁴²), sun sensitivity (OR=2.94), and freckling (OR=4.37). R151C is found in 93% of individuals with red hair¹⁴¹⁴ found in 93% of individuals with red hair
along with R160W and D294H, accounts for the vast majority of red hair phenotype.

Practical Implications

If you carry two copies of the T allele (TT genotype), inform your anesthesiologist and dentist. The 19-20% increase in anesthetic requirement is clinically significant and can mean the difference between adequate and inadequate sedation during procedures. This isn't hypersensitivity or anxiety — it's a well-documented pharmacogenetic effect requiring dose adjustment.

For skin cancer prevention, individuals with R151C variants need rigorous sun protection independent of visible phenotype¹⁵¹⁵ rigorous sun protection independent of visible phenotype
even darker-skinned MC1R variant carriers show increased melanoma risk. The increased melanoma risk persists even after accounting for skin type, suggesting mechanisms beyond UV-related damage.

The paradoxical pain response — increased sensitivity in some contexts but enhanced opioid analgesia in others — suggests multimodal pain management may be particularly important for MC1R variant carriers. Women with two variant alleles may benefit from kappa-opioid analgesics like pentazocine for certain pain types.

Interactions

MC1R shows strong compound heterozygosity effects: carrying two different MC1R loss-of-function variants (e.g., R151C on one chromosome and R160W on another) produces the full red hair phenotype and associated clinical effects, just like being homozygous for a single variant. The most common compound genotypes involve R151C + R160W (rs1805008), R151C + D294H (rs1805009), or R151C + R142H. Studies show heterozygotes for two different MC1R variants have significantly elevated risk of red hair¹⁶¹⁶ heterozygotes for two different MC1R variants have significantly elevated risk of red hair
Flanagan et al. demonstrated compound heterozygotes show effects between heterozygotes and homozygotes.

For melanoma risk, MC1R variants interact with CDKN2A mutations (p16-Leiden deletion). In families with p16 mutations, MC1R variants including R151C substantially increase penetrance¹⁷¹⁷ MC1R variants including R151C substantially increase penetrance
MC1R variants doubled melanoma risk in p16 mutation carriers, doubling the risk of melanoma development. This suggests that individuals with family history of melanoma and MC1R variants may warrant enhanced surveillance.