rs139315125 — PER3 H417R

PER3 H417R — The Second Blow to the Circadian Clock

The PER3 gene¹¹ PER3 gene
Period Circadian Regulator 3, one of the three Period proteins forming the negative feedback arm of the molecular circadian clock encodes a protein that accumulates during the day, translocates into the nucleus, and represses the CLOCK-BMAL1 transcription complex that drove its own synthesis — completing one full oscillation every ~24 hours. The rs139315125 variant introduces an arginine at position 417 where histidine normally sits, and it almost always arrives in combination with the rs150812083 Pro415Ala change, seven base pairs upstream on the same chromosome copy.

On its own, H417R is classified as conflicting significance in ClinVar — most recent submissions rate it as uncertain or likely benign, reflecting the difficulty of deconvolving individual contributions when the two changes always co-occur. Its primary clinical importance is as the second component of the compound P415A/H417R haplotype that causes familial advanced sleep phase syndrome 3 (FASPS3)²² familial advanced sleep phase syndrome 3 (FASPS3)
An autosomal dominant circadian rhythm disorder characterized by sleep onset 4-6 hours earlier than population average, with spontaneous waking around 4 AM, and associated seasonal mood vulnerability.

The Mechanism

PER3 protein stability depends critically on the local structure of its PAS domain³³ PAS domain
PER-ARNT-SIM domain — a conserved protein-protein interaction module shared across clock proteins, used by PER proteins to dimerize and interact with CRY repressor partners. At position 417, histidine contributes to the hydrogen-bonding network that stabilizes this domain. The G allele substitutes the positively charged, bulkier arginine, perturbing the local fold and — when combined with the adjacent Pro415Ala substitution — produces a protein that degrades faster and accumulates to lower nuclear concentrations despite elevated mRNA production.

Zhang et al. (PNAS, 2016)⁴⁴ 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. showed that PER3-P415A/H417R has reduced transcriptional repressor activity across multiple titers compared with wild-type PER3, and loses the ability to stabilize both PER1 and PER2 — compounding the clock acceleration. Transgenic mice expressing the compound human allele showed altered circadian period under constant light conditions and depression-like behavior under short photoperiod, directly linking the destabilized PER3 to seasonal affective phenotypes.

The Evidence

The P415A/H417R compound haplotype was characterized in a three-generation family with FASPS3 by Zhang et al. (PNAS 2016, PMID 26903630). Affected members fell asleep by midnight and woke spontaneously by 8:15 AM (~4 hours earlier than average), and scored at the 97th–99th percentile for seasonal mood variation with worst symptoms in December and January. All published functional studies tested the two substitutions together; the individual contribution of H417R alone was not deconvolved, which explains the conflicting ClinVar classifications.

At the population level, the G allele of rs139315125 is rare: ~0.58% in Europeans, ~0.04% in Africans, and ~0.005% in East Asians (gnomAD exomes). Given the near- perfect co-occurrence with rs150812083 G on the same chromosome, allele frequencies and phenotypic associations are effectively shared between the two entries. The Jones et al. 2019 GWAS (Nature Communications, 697,828 individuals) identified the PER3 locus as contributing to extreme morningness chronotype with an odds ratio of 1.44, and objective sleep timing ~8 minutes earlier by actigraphy.

ClinVar accession VCV000242411 currently reflects conflicting classifications (1 pathogenic, 2 uncertain significance, 1 likely benign), with the pathogenic call resting on co-segregation in the FASPS3 family; the uncertain and likely benign calls reflect the difficulty of attributing causality to one variant when it always co-occurs with a second.

Practical Implications

Carriers of this variant who do not also carry the rs150812083 G allele face genuinely uncertain phenotypic impact — the functional evidence is for the compound haplotype. Carriers who are positive at both positions have a biologically accelerated clock: an intrinsic circadian period shorter than 24 hours that advances the entire sleep-wake cycle. The degree of phase advance varies with environment and other genetic modifiers, but the affected FASPS3 family consistently showed 4-hour advances.

Evening bright light therapy — exposure between 7 and 9 PM — is the most evidence-supported intervention for advanced sleep phase. Light in this window falls in the phase-delay zone of the circadian phase response curve⁵⁵ circadian phase response curve
The PRC describes how light exposure at different clock times shifts the circadian oscillator; late-evening light delays the clock, early-morning light advances it, counteracting the pathological advance. Avoiding bright light in the first hour after waking prevents compounding the phase shift further.

Interactions

rs139315125 (H417R) and rs150812083 (Pro415Ala) sit seven base pairs apart and are almost always inherited together on the same chromosome as the FASPS3 compound haplotype. Functionally, both changes contribute to PER3 protein destabilization; the compound state produces more severe clock acceleration than either change alone based on current evidence.

The same circadian feedback loop involves rs228697 (PER3 Pro864Ala), which lengthens circadian period (evening-shifting) rather than shortening it. An individual carrying both an evening-shifting PER3 variant and this morning- advancing haplotype would experience opposing molecular forces, potentially producing an unstable or irregular circadian rhythm. rs35333999 (PER2 V903I) is another evening-shifting component in the same repressor complex.

The seasonal mood dimension creates a plausible interaction with melatonin pathway variants, particularly rs10830963 (MTNR1B), though no published study has formally characterized compound H417R/MTNR1B carriers.