rs2304672 — PER2 5'UTR C111G

PER2 C111G — Your Internal Clock's Fine-Tuning Dial

The PER2 gene is one of the central gears in your body's circadian clock¹¹ circadian clock
The ~24-hour internal timer that governs sleep-wake cycles, hormone release, body temperature, and metabolism. It runs in nearly every cell but is coordinated by the suprachiasmatic nucleus (SCN) in the brain. Every day, PER2 protein levels rise and fall in a precise rhythm: the protein accumulates, enters the nucleus to shut down its own gene, gets degraded, and the cycle starts again. This molecular oscillation is the heartbeat of circadian timing. The rs2304672 variant sits in the 5' UTR²² 5' UTR
5' untranslated region: the stretch of mRNA before the protein-coding sequence begins. It doesn't change the protein itself but can alter how much protein gets made and when of PER2, 12 bases upstream of where translation begins, positioning it to influence how much PER2 protein your cells produce.

The Mechanism

Unlike the famous PER2 S662G mutation that causes Familial Advanced Sleep Phase Syndrome³³ Familial Advanced Sleep Phase Syndrome
FASPS: a rare inherited condition where affected individuals fall asleep around 7:30 PM and wake at 4:30 AM. Caused by a missense mutation that alters PER2 phosphorylation and degradation, rs2304672 does not change the PER2 protein itself. Instead, it sits in the 5' UTR regulatory region where it can affect mRNA stability, translation efficiency, or transcription factor binding. The C allele (plus strand; called "111G" in the original literature, which used mRNA strand notation⁴⁴ mRNA strand notation
PER2 is on the minus strand of chromosome 2. The "C111G" name describes the change on the mRNA/coding strand: C (common) to G (variant). On the plus strand that 23andMe reports, this is reversed: G (common) to C (variant)) has been associated with lower PER2 expression in thyroid tissue, suggesting it may subtly reduce PER2 protein levels. Since PER2 is a transcriptional repressor⁵⁵ transcriptional repressor
PER2 protein accumulates and then enters the nucleus where it inhibits CLOCK/BMAL1, the transcription factors that activated PER2 in the first place. This negative feedback loop is the core engine of the circadian clock in the clock feedback loop, reduced levels could advance the phase of the oscillation, shifting the entire sleep-wake cycle earlier.

The Evidence

The original discovery⁶⁶ original discovery
Carpen JD et al. A single-nucleotide polymorphism in the 5'-untranslated region of the hPER2 gene is associated with diurnal preference. J Sleep Res, 2005 came from a UK study at the University of Surrey. Among 484 volunteers screened for extreme chronotype, the C allele (plus strand) was found at 14% frequency in extreme morning types but only 3% in extreme evening types (OR 5.67, P = 0.031). This made rs2304672 one of the first common variants linked to human chronotype.

Replication has been mixed. A Korean study of 299 medical students⁷⁷ Korean study of 299 medical students
Lee HJ et al. PER2 variation is associated with diurnal preference in a Korean young population. Behav Genet, 2011 found no significant association, though the authors noted the minor allele frequency was very low in their East Asian sample (8.4%), limiting statistical power. A Swedish study of over 1,200 individuals⁸⁸ Swedish study of over 1,200 individuals
Johansson AS et al. PER gene family polymorphisms in relation to cluster headache and circadian rhythm in Sweden. Brain Sci, 2021 found a minor allele frequency of ~12% in European controls but no association with cluster headache or chronotype in that cohort.

Beyond chronotype, neuroimaging research in 90 adolescents⁹⁹ neuroimaging research in 90 adolescents
Forbes EE et al. PER2 rs2304672 polymorphism moderates circadian-relevant reward circuitry activity in adolescents. Biol Psychiatry, 2012 revealed that C allele carriers showed reduced medial prefrontal cortex¹⁰¹⁰ medial prefrontal cortex
mPFC: a brain region involved in reward evaluation, decision-making, and emotional regulation. It integrates circadian signals with motivational states activity during reward processing, and this effect was modulated by sleep timing. Later sleep midpoints amplified the difference between genotypes, suggesting that the variant's impact on brain function depends on alignment with circadian phase.

A UK twin study of 862 participants¹¹¹¹ UK twin study of 862 participants
Denis D et al. A twin and molecular genetics study of sleep paralysis and associated factors. J Sleep Res, 2015 found a nominally significant association between rs2304672 and sleep paralysis (P = 0.008, additive model), though this did not survive correction for multiple testing. The connection is plausible: sleep paralysis involves dysregulated transitions between sleep stages, which are under circadian control.

Practical Implications

This variant has a modest effect size and mixed replication, placing it firmly in the "worth knowing, not life-changing" category. If you carry one or two copies of the C allele, you may have a natural tendency toward earlier sleep timing. This is not deterministic: light exposure, meal timing, exercise, and social schedule all powerfully shape your circadian phase. But working with your genetic tendency rather than against it can improve sleep quality and daytime alertness.

The reward circuitry findings suggest that C allele carriers may be more sensitive to the cognitive effects of misaligned sleep. If you are a carrier who keeps a late schedule (fighting your biological clock), you may notice stronger effects on mood and motivation than a non-carrier would in the same situation.

Interactions

PER2 operates within a network of clock genes. CLOCK (rs1801260) drives PER2 transcription as part of the CLOCK/BMAL1 activator complex, while PER3 (rs57875989) is a paralog with its own circadian associations. Carriers of both the PER2 rs2304672 C allele and the CLOCK rs1801260 G allele (evening preference allele) may experience a push-pull effect on chronotype, with the net result depending on which signal dominates. Studies examining these variants together are limited but the biological rationale for interaction is strong, given that PER2 and CLOCK sit on opposite sides of the same feedback loop.