PER3 H417R — The Second Blow to the Circadian Clock
The 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) | 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 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) | 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 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.
Alla genotyper
Normal PER3 H417 — no FASPS3 haplotype contribution from this variant
You carry two copies of the common A allele at rs139315125, producing histidine at position 417 of the PER3 protein — the standard, stable configuration. This variant does not contribute to circadian period shortening or advanced sleep phase. Approximately 99% of people carry this genotype. Your sleep timing and seasonal mood regulation are not affected by this particular PER3 variant. Other genetic and lifestyle factors determine your individual chronotype.
One copy of H417R — part of the FASPS3 haplotype associated with earlier sleep timing and seasonal mood sensitivity
You carry one copy of the G allele at rs139315125, introducing arginine at position 417 of PER3. This change almost always co-occurs with the adjacent Pro415Ala substitution (rs150812083) on the same chromosome, forming the compound P415A/H417R haplotype that causes familial advanced sleep phase syndrome 3 (FASPS3). The combined haplotype destabilizes PER3 protein, accelerates the molecular clock, and advances sleep timing. Approximately 1% of people of European ancestry carry a G allele here, and the phenotypic severity for the compound haplotype — where documented — includes falling asleep by midnight, waking spontaneously by 8:15 AM (approximately 4 hours earlier than average), and seasonality scores at the 97th–99th percentile for winter-pattern mood variation.
Two copies of H417R — extremely rare, consistent with severe FASPS3 haplotype homozygosity
You carry two copies of the G allele at rs139315125. Given the G allele frequency of ~0.5% globally, GG homozygosity is expected in roughly 1 in 40,000 people. No published studies have specifically characterized GG homozygotes for this variant; all FASPS3 clinical descriptions come from heterozygous carriers of the compound P415A/H417R haplotype. With both PER3 copies producing the H417R protein — and almost certainly also the adjacent Pro415Ala change — neither copy can fulfill PER3's stabilizing and repressor role in the circadian feedback loop. Clock acceleration would be expected to be more severe than in heterozygotes, with potentially more extreme phase advance and greater seasonal mood vulnerability.