rs150812083 — PER3 PER3 Pro415Ala (FASPS3)

Rare PER3 missense variant that destabilizes the circadian clock protein, shortening circadian period and causing familial advanced sleep phase syndrome 3 with associated seasonal mood vulnerability

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PER3 Pro415Ala — The Ultra-Early-Riser Variant

The PER3 gene11 PER3 gene
Period Circadian Regulator 3, one of three Period proteins that form the negative feedback arm of the molecular circadian clock is a master timekeeper in every cell of your body. Its protein accumulates during the day, enters the nucleus, and shuts down the very transcription machinery that made it — completing one oscillation roughly every 24 hours. The rs150812083 variant swaps a proline for an alanine at position 415, and the consequences reach all the way from molecular clock mechanics to sleep timing, seasonal mood, and family history of early-rising disorder.

This variant is rare — found in roughly 1 in 200 people of European descent — but its effect is dramatic. It was first identified as the cause of familial advanced sleep phase syndrome 3 (FASPS3)22 familial advanced sleep phase syndrome 3 (FASPS3)
An autosomal dominant circadian rhythm disorder in which affected individuals fall asleep and wake approximately 4 hours earlier than average, with sleep onset around 6-8 PM and spontaneous waking around 4 AM, and later confirmed as a strong morningness signal in the largest chronotype GWAS to date.

The Mechanism

At position 415, proline is a structurally rigid amino acid that imposes a sharp bend in the local protein chain. The G allele substitutes the flexible alanine, disrupting a conserved region near the CRY-binding interface33 CRY-binding interface
CRY1/CRY2 proteins partner with PER proteins to form the transcriptional repressor complex that feeds back to inhibit CLOCK-BMAL1 activity.

The functional consequence, shown in Zhang et al. 201644 Zhang et al. 2016
Zhang L et al. A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait. PNAS, 2016., is counterintuitive: the Pro415Ala protein is less stable than wild-type — it degrades faster, accumulates to lower nuclear levels despite higher mRNA production, and loses repressor efficiency. Without sufficient PER3 to dampen the CLOCK-BMAL1 feedback loop, the clock cycles more rapidly — shortening the intrinsic circadian period and advancing the entire sleep-wake cycle.

The same variant also impairs PER3's ability to stabilize PER1 and PER2 proteins, compounding the clock acceleration. Transgenic mice expressing the human P415A/H417R allele showed an altered circadian period under constant light conditions and, strikingly, showed phase-shifted activity and depression-like behavior in short photoperiod conditions mimicking winter — directly linking this circadian variant to seasonal affective disorder (SAD).

The Evidence

The variant was first described in a three-generation family with FASPS3 by Zhang et al. (PNAS, 2016)55 Zhang et al. (PNAS, 2016)
Zhang L et al. A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait. PNAS 113(11):E1536-44.. Affected members fell asleep by midnight and woke spontaneously by 8:15 AM (advanced by ~4 hours relative to population average), and scored at the 99th percentile for seasonal mood variation — with worst symptoms in December and January. The variant co-occurs on the same chromosome copy as a second change (rs139315125, H417R); in vitro studies showed both positions contribute to protein destabilization.

At the population scale, Jones et al. (Nature Communications, 2019)66 Jones et al. (Nature Communications, 2019)
Jones SE et al. Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms. Nat Commun 10:343. found the G allele associated with self-reported morningness at extraordinary significance (OR=1.44, P=2×10⁻³⁸) in a meta-analysis of UK Biobank and 23andMe participants — making it one of the strongest single-variant effects on chronotype ever identified. Notably, the objective effect on sleep timing was modest (~8 minutes earlier by actigraphy), suggesting the variant's primary impact on subjective sleep experience is disproportionate to its absolute phase advance.

Practical Implications

Carriers of the G allele experience a genuine biological drive toward earlier sleep timing. Unlike lifestyle-driven early rising, this variant reflects an intrinsically faster molecular clock. The clinical consequence depends on whether your environment accommodates your advanced phase:

Early timing aligns well with standard work and school schedules, but creates problems in social contexts demanding late-night participation. The more serious concern is the seasonal mood dimension. Because PER3 governs how the circadian clock adapts to photoperiod (day length), a destabilized PER3 may impair seasonal adaptation — the same mechanism that causes winter-pattern SAD. G allele carriers in the FASPS3 family showed seasonality scores above the 97th percentile, with winter depression.

Evening bright light therapy is the most evidence-supported intervention for FASPS: light between 7 and 9 PM shifts the phase-delaying window of the circadian phase response curve77 circadian phase response curve
The PRC describes how light exposure at different clock times shifts the circadian phase; light in the evening hours (the delay zone) pushes the clock later, counteracting the pathological advance. Morning bright light avoidance (or blue-light filtering) prevents further clock advancement on waking.

Interactions

This variant is reported on the same haplotype as rs139315125 (H417R in PER3), seven base pairs downstream. The two changes consistently co-occur in published FASPS3 families and functional studies always test them together. Either variant alone may have attenuated effects; the compound haplotype is the clinically relevant combination.

PER3 Pro415Ala sits in the same feedback loop as rs228697 (PER3 Pro864Ala) and rs35333999 (PER2 V903I). Those variants lengthen circadian period (evening-shifting), while rs150812083 shortens it (morning-shifting). An individual carrying both an evening-shifting PER2 variant and this advanced-phase PER3 variant would experience opposing forces, potentially producing an unstable or irregular circadian rhythm rather than a clean chronotype in either direction.

The seasonal mood dimension suggests potential interaction with melatonin pathway variants such as rs10830963 (MTNR1B) and serotonin transporter variants; no published studies have formally characterized these gene-gene interactions.

Genotype Interpretations

What each possible genotype means for this variant.

CC Standard Clock Normal

Normal PER3 stability — no advanced sleep phase tendency from this variant

You have two copies of the common C allele, producing proline at position 415 of the PER3 protein. Your PER3 protein has normal stability and repressor function, and your circadian clock is not accelerated by this variant. This is the most common genotype — approximately 99% of people carry it.

Your sleep timing and seasonal mood regulation are not affected by this particular PER3 variant. Other genetic and lifestyle factors determine your individual chronotype.

CG FASPS3 Carrier Carrier

One copy of the Pro415Ala variant — biologically earlier sleep timing and possible seasonal mood sensitivity

The Pro415Ala substitution destabilizes the PER3 protein: it degrades faster, accumulates to lower nuclear levels despite elevated mRNA, and loses its ability to stabilize PER1 and PER2. The net result is reduced repression of the CLOCK-BMAL1 transcription complex, which shortens the intrinsic circadian period and shifts the entire sleep-wake cycle earlier.

The clinical presentation ranges from a mild extreme-morning chronotype to full familial advanced sleep phase syndrome 3 (FASPS3), depending on penetrance and environment. The strongest documented effect is on subjective morningness (OR=1.44 in 697,828 individuals); the objective sleep-timing advance measured by actigraphy was ~8 minutes — modest in absolute terms but statistically extraordinary.

The seasonal affective dimension is clinically important: PER3 also governs photoperiodic adaptation. Zhang et al. showed that mice expressing the P415A/H417R allele developed depression-like behavior specifically under short photoperiod (winter-like) conditions, reversible with antidepressant treatment. The three affected human family members reported their worst mood in December and January, with seasonality scores at the 96.9–99.99th percentile.

GG FASPS3 Homozygous Homozygous

Two copies of the Pro415Ala variant — extremely rare, profound clock acceleration expected

With both copies of PER3 producing the unstable alanine-415 protein, neither copy can adequately fulfill PER3's role in stabilizing PER1 and PER2 or repressing CLOCK-BMAL1 activity. The result would be a maximally accelerated circadian clock — a profound phase advance of the entire sleep-wake cycle.

In the FASPS3 family studied by Zhang et al. 2016, heterozygous carriers already showed 4-hour phase advances and 97th-percentile seasonality scores. Homozygous status, though not documented in published literature, would be expected to produce more severe phenotypes. Referral to a specialized sleep medicine or circadian rhythm clinic is appropriate for clinical evaluation and guided management.