rs228697 — PER3 Pro864Ala

PER3 Pro864Ala — Your Internal Clock's Tempo

The PER3 gene encodes Period Circadian Regulator 3¹¹ Period Circadian Regulator 3
One of three Period proteins (PER1, PER2, PER3) that form the negative arm of the mammalian circadian clock feedback loop, a protein at the heart of the molecular clock that governs your ~24-hour sleep-wake cycle. Every cell in your body runs a version of this clock, and PER3 helps set its tempo. The rs228697 variant swaps a proline for an alanine at position 864, subtly changing how the clock protein behaves — and, with it, whether you lean toward being a morning lark or a night owl.

PER3 is best known for its VNTR polymorphism²² VNTR polymorphism
A variable number tandem repeat (4 or 5 copies of a 54-bp repeat) in exon 18 that strongly influences sleep timing and homeostatic sleep drive, but is not on SNP genotyping chips (4-repeat vs 5-repeat), which strongly predicts sleep timing and sleep need but cannot be genotyped on standard SNP chips. The Pro864Ala missense variant (rs228697) is the best SNP-chip proxy for PER3 circadian effects and has its own independent functional consequences.

The Mechanism

The circadian clock runs on a transcription-translation feedback loop³³ transcription-translation feedback loop
CLOCK and BMAL1 proteins activate transcription of PER and CRY genes; the PER/CRY protein complex then feeds back to repress CLOCK-BMAL1, creating a ~24-hour oscillation. CLOCK and BMAL1 proteins bind to E-box elements⁴⁴ E-box elements
Short DNA sequences (CACGTG) in gene promoters that CLOCK-BMAL1 heterodimers recognize to activate transcription of clock-controlled genes to activate PER and CRY genes. The resulting PER and CRY proteins accumulate, form complexes, enter the nucleus, and repress their own transcription — completing one cycle roughly every 24 hours.

The Pro864Ala substitution sits in a region containing two potential SH3-binding motifs⁵⁵ SH3-binding motifs
Src Homology 3 domains mediate protein-protein interactions; the proline-to-alanine change disrupts these binding sites, altering how PER3 interacts with partner proteins. Replacing proline (a rigid amino acid that enforces tight bends in protein structure) with alanine (a flexible, small amino acid) alters the local protein conformation. Functional experiments⁶⁶ Functional experiments
Lavebratt C et al. Molecular analyses of circadian gene variants. Transl Psychiatry, 2016 showed that the variant (G allele) protein is more stable than the wild-type — it degrades more slowly, accumulates to higher levels, and recruits more PER2 into the transcription repression complex. The result is a stronger repressor of CLOCK-BMAL1-driven transcription.

When the variant hPER3 was expressed in mammalian fibroblasts, it caused a significant, dose-dependent lengthening of the circadian period. A computational model⁷⁷ computational model
Liberman AR et al. Circadian clock model supports molecular link between PER3 and human anxiety. Sci Rep, 2017 estimated this lengthening at 2-6% — enough to shift a 24-hour period toward roughly 25 hours. People whose internal clock runs long tend to drift toward later sleep and wake times — the hallmark of evening chronotype.

The Evidence

The initial genetic association⁸⁸ initial genetic association
Hida A et al. Screening of clock gene polymorphisms demonstrates association of a PER3 polymorphism with morningness-eveningness preference and circadian rhythm sleep disorder. Sci Rep, 2014 came from a Japanese study of 925 controls, 182 delayed sleep phase patients, and 67 free-running type patients. The G allele was significantly associated with eveningness preference (sex-adjusted OR 2.48, 95% CI 1.34-4.60, corrected P = 0.012). More strikingly, G allele frequency was doubled in free-running type patients — people whose internal clock fails to entrain to the 24-hour day (age- and sex-adjusted OR 2.02, 95% CI 1.16-3.52, P = 0.017).

An Italian replication study⁹⁹ Italian replication study
Lazar AS et al. Diurnal preference, mood and the response to morning light in relation to polymorphisms in the human clock gene PER3. Sci Rep, 2017 of 786 Caucasian subjects confirmed the chronotype association (OR 2.10, 95% CI 1.21-3.65, P = 0.008) and found that G carriers showed lower mood scores in the late afternoon and early evening — the time when a longer-period clock would be most misaligned with the external day.

Beyond chronotype, a case-control study¹⁰¹⁰ case-control study
Lavebratt C et al. Molecular analyses of circadian gene variants reveal sex-dependent links between depression and clocks. Transl Psychiatry, 2016 of 592 major depressive disorder (MDD) cases and 776 controls found the G allele associated with MDD risk (OR 1.39, allelic P = 0.007), with a stronger effect in women (allelic P = 0.041). Separately, anxiety levels¹¹¹¹ anxiety levels
Liberman AR et al. Sci Rep, 2017 were significantly higher in G allele carriers (F(2,305) = 3.195, P = 0.042), consistent with the broader finding that circadian misalignment elevates anxiety and depression risk.

Practical Implications

This variant does not cause disease. It shifts your circadian tendency. If you carry the G allele and find yourself naturally gravitating toward later bedtimes, the biology supports what you already feel. The key is to work with your chronotype rather than fight it:

Morning light exposure is the most powerful tool for advancing a late-running clock. Even 20-30 minutes of outdoor light before 10 AM can shift your circadian phase earlier. Conversely, avoiding bright light (especially blue-enriched screens) in the 2-3 hours before desired bedtime prevents the clock from being pushed even later.

Meal timing also entrains peripheral clocks. Eating your last substantial meal at least 3 hours before sleep, and anchoring breakfast to a consistent time, provides a secondary timing cue that reinforces the light signal.

For the mood dimension, the association between this variant and depression/anxiety appears to operate through circadian misalignment rather than a direct effect on mood neurocircuitry. Maintaining regular sleep-wake timing — even on weekends — reduces social jetlag¹²¹² social jetlag
The discrepancy between your biological clock and your social schedule, measured as the difference between midpoint of sleep on work days vs free days and may mitigate the mood risk.

Interactions

PER3 Pro864Ala interacts with the PER3 VNTR (4-repeat vs 5-repeat). The G allele combined with the PER3-4 repeat haplotype shows a stronger association with morningness than either variant alone (OR 2.19 for the haplotype vs OR 2.10 for the SNP alone). However, the VNTR is not genotyped on standard SNP chips, so this interaction cannot be assessed from 23andMe data.

PER3 is part of a broader circadian gene network including CLOCK, BMAL1 (ARNTL), PER1, PER2, CRY1, and CRY2. Variants in these genes may compound or buffer PER3 effects on chronotype, but specific SNP-SNP interactions with rs228697 have not been well characterized in the published literature.