rs35333999 — PER2 V903I

Missense variant in core circadian clock gene PER2 that lengthens intrinsic circadian period and shifts chronotype toward eveningness

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PER2 V903I — The Night Owl Clock Variant

The PER2 gene encodes Period Circadian Regulator 211 Period Circadian Regulator 2
One of three Period proteins forming the core negative feedback arm of the mammalian circadian clock, suppressing CLOCK:BMAL1-driven transcription, one of the master gears of your internal 24-hour clock. PER2 protein accumulates during the day, enters the nucleus, and shuts down the CLOCK:BMAL1 transcription complex — resetting the cycle. The rs35333999 variant changes a valine to isoleucine at position 903.

This variant is notable because it is the strongest association signal that peaks directly within a core circadian clock gene in genome-wide association studies of chronotype. Most chronotype GWAS signals map to regulatory or intergenic regions — PER2 V903I is a coding change in the heart of the clock machinery.

The Mechanism

The V903I substitution alters a conserved valine in exon 19 of the canonical PER2 transcript. Computational analysis predicts this change as probably damaging22 Computational analysis predicts this change as probably damaging
PolyPhen-2 score of 0.963, indicating high likelihood of functional impact. The valine-to-isoleucine change is conservative (both are hydrophobic branched-chain amino acids), but the position is conserved across mammalian species33 conserved across mammalian species
suggesting functional constraint at this site.

The functional consequence is a measurable lengthening of intrinsic circadian period — the fundamental oscillation speed of the molecular clock. A longer period means the clock "runs slow," requiring more environmental resetting (via light) each day to stay synchronized with the 24-hour world. When the clock runs slow, the natural tendency is to drift later — later sleep onset, later wake time, and a preference for evening activity.

The Evidence

The key study establishing both population-level chronotype association and mechanistic causation was Chang et al. 201944 Chang et al. 2019
Chang A-M et al. Chronotype Genetic Variant in PER2 is Associated with Intrinsic Circadian Period in Humans. Sci Rep, 2019. This study combined large-scale GWAS data with precisely controlled laboratory measurements:

In the UK Biobank cohort of 335,789 individuals55 UK Biobank cohort of 335,789 individuals
unrelated participants of European ancestry, the T allele reached genome-wide significance for self-reported eveningness (P = 9.7 x 10-14, beta = 0.058).

The same study then measured intrinsic circadian period in a subset of participants under highly controlled forced desynchrony protocols66 forced desynchrony protocols
Laboratory protocols where participants live on non-24-hour schedules to unmask the endogenous circadian period from environmental time cues. T allele carriers showed a 12-minute longer circadian period by both core body temperature77 core body temperature
24.34 +/- 0.17 h vs 24.14 +/- 0.20 h, P = 0.030 and plasma melatonin88 plasma melatonin
24.34 +/- 0.18 h vs 24.15 +/- 0.19 h, P = 0.039 measurements. The variant accounted for approximately 7% of inter-individual variance in circadian period — a substantial effect for a single SNP.

Practical Implications

A 12-minute longer circadian period may sound small, but it compounds daily. Without sufficient morning light exposure to reset the clock each day, carriers drift progressively later. This has real consequences for metabolic health: evening chronotypes consistently show higher rates of type 2 diabetes, obesity, and cardiovascular disease in epidemiological studies, driven by late eating, disrupted meal-activity synchronization, and social jet lag.

Interactions

PER2 V903I interacts functionally with other circadian clock gene variants. The CLOCK rs1801260 G allele increases CLOCK protein levels, potentially amplifying PER2 expression; combined with a PER2 variant that slows the clock, the result could be additive circadian delay. Similarly, PER3 rs228697 (Pro864Ala) and PER3 rs10462020 (Val647Gly) affect the Period protein arm of the same feedback loop. Carriers of multiple evening-shifting alleles across PER2, PER3, and CLOCK likely experience more pronounced circadian delay than any single variant predicts.

Compound implication for PER2 rs35333999 + CLOCK rs1801260: Individuals carrying both the PER2 T allele (CT or TT) and the CLOCK G allele (AG or GG) may experience compounded evening-shifting effects — both increased CLOCK protein driving the positive limb and a slowed PER2 negative feedback loop. These carriers would benefit most from aggressive morning light exposure and strict meal timing.

Genotype Interpretations

What each possible genotype means for this variant.

CC Standard Clock Normal

Normal PER2 protein and standard circadian period length

With the CC genotype, your PER2 protein contains the ancestral valine at position 903. Your intrinsic circadian period, as measured in controlled laboratory settings, averages approximately 24.14 hours — close to the 24-hour solar day — meaning minimal daily resetting is needed.

In the UK Biobank, CC homozygotes score higher on morningness-eveningness questionnaires on average compared to T allele carriers, though individual chronotype is influenced by many genes and environmental factors.

CT Longer Clock Intermediate

One copy of the variant extends your circadian period by approximately 12 minutes

The V903I change in one copy of your PER2 gene produces a measurably longer circadian period. In Chang et al. 2019, heterozygous carriers showed circadian periods averaging 24.34 hours by core body temperature measurement, compared to 24.14 hours in non-carriers (P = 0.030). This 12-minute difference means your clock needs more environmental input each day to stay synchronized with the solar cycle.

This variant accounted for approximately 7% of inter-individual variance in circadian period — a large effect for a single SNP. The T allele reached genome-wide significance for evening chronotype in 335,789 UK Biobank participants (P = 9.7 x 10-14).

TT Extended Clock High

Two copies of the variant produce maximal circadian period lengthening

With two copies of the V903I variant, both PER2 proteins carry the isoleucine substitution. While no study has specifically measured circadian period in TT homozygotes (they are too rare for most study designs), the codominant inheritance pattern and the measured 12-minute effect in heterozygotes suggest a larger period extension in homozygotes.

TT homozygotes were too rare (expected frequency ~0.2%) to analyze separately in the UK Biobank study, but the additive model showed a clear dose-response: each T allele shifted chronotype significantly toward eveningness (beta = 0.058 per allele).

This genotype is essentially absent in East Asian populations and extremely rare in African and South Asian populations; it is primarily found in individuals of European ancestry.