rs184039278 — CRY1 CRY1Δ11

Splice-site variant in the circadian clock gene CRY1 that causes exon 11 skipping, producing a gain-of-function protein that lengthens circadian period by ~30 minutes and drives Delayed Sleep Phase Disorder

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CRY1Δ11 — The Night-Owl Gene That Runs Your Clock 30 Minutes Slow

Inside every cell of your body ticks a molecular clock, cycling with almost perfect 24-hour precision. The CRY1 protein is one of its master regulators — a transcriptional brake that keeps the CLOCK:BMAL1 activator complex from running perpetually. The CRY1Δ11 variant (c.1657+3A>C on the coding strand, NC_000012.12:g.106992962T>G11 NC_000012.12:g.106992962T>G
genomic HGVS notation, GRCh38 plus strand) disrupts a splice site at the boundary of intron 11, causing the entire exon 11 to be skipped during mRNA processing. The result is a CRY1 protein missing 24 amino acids from its C-terminal tail — and it is more powerful, not less. This gain-of-function makes the mutant CRY1 cling more tightly to CLOCK and BMAL1, prolonging transcriptional inhibition and stretching the molecular clock period from 24 hours to roughly 24.5 hours. Half an hour per cycle compounds: carriers' sleep timing drifts 2–2.5 hours later than their circadian phase actually warrants22 carriers' sleep timing drifts 2–2.5 hours later than their circadian phase actually warrants
Patke et al. Cell 2017, producing the signature symptom of Delayed Sleep Phase Disorder.

The Mechanism

The 5' splice site of intron 11 contains the sequence the spliceosome uses to remove intron 11 and join exon 11 to exon 12. The c.1657+3A>C transversion weakens this recognition sequence enough that the spliceosome skips exon 11 entirely. The resulting mRNA encodes a CRY1 protein with an in-frame 24-amino acid deletion in the C-terminal tail domain33 tail domain
The C-terminal tail modulates CRY1's interaction surface with CLOCK and BMAL1. Counterintuitively, this deletion enhances rather than impairs CRY1's function. The mutant protein localizes to the nucleus more readily than wild-type CRY1, occupies CLOCK:BMAL1 binding sites on chromatin for longer, and suppresses transcription of circadian target genes — including Per1, Per2, and Dbp — more persistently. Chromatin immunoprecipitation studies showed the mutant CRY1 displaced CLOCK and BMAL1 from their target gene promoters44 Chromatin immunoprecipitation studies showed the mutant CRY1 displaced CLOCK and BMAL1 from their target gene promoters
Consistent with a dominant gain-of-function mechanism. The net effect is a circadian period that runs slow, anchoring the person's internal clock later and later relative to the external light-dark cycle.

The Evidence

The founding study by Patke et al. in Cell (2017)55 Patke et al. in Cell (2017)
PMID 28388406 identified CRY1Δ11 in affected members of seven unrelated Turkish families with familial DSPD. In a validation cohort of 70 subjects from six families (8 homozygous carriers, 31 heterozygous carriers, 31 non-carriers), the variant segregated with DSPD with a Fisher's exact P < 0.0001 and an odds ratio of 1,928 — an effect size rarely seen in common-disease genetics. In temporal isolation experiments, the proband's free-running circadian period measured 24.52 hours. In vitro, mouse embryonic fibroblasts expressing the mutant CRY1 showed a period lengthened by approximately 30 minutes relative to cells expressing wild-type CRY1. The variant frequency in the gnomAD database is approximately 0.4% globally, rising to 0.65% in non-Finnish Europeans and ~3% in Ashkenazi Jewish populations, consistent with Patke et al.'s estimate that roughly 1 in 75 people of certain ancestries carry this allele66 Patke et al.'s estimate that roughly 1 in 75 people of certain ancestries carry this allele
Making it one of the most common single-gene causes of a sleep disorder ever identified.

A follow-up observational study by Smieszek et al. (2021)77 observational study by Smieszek et al. (2021)
Sci Rep, PMID 34635699 enrolled 67 participants (33 CRY1Δ11 carriers, 34 wild-type controls) from Turkish families and confirmed that carriers had significantly later wake times, sleep midpoints, and longer sleep-onset latency. Remarkably, the circadian delay extended to metabolic outputs: bowel movement timing was approximately 91 minutes later in carriers (p = 0.002), demonstrating that the lengthened period affects the entire peripheral clock network, not just the central sleep-wake system.

A 2020 study by Onat et al. in JCI88 Onat et al. in JCI
PMID 32538895 extended the phenotype. Among 96 individuals from 12 Turkish families with combined ADHD and DSPD, CRY1Δ11 was present in 13% of affected individuals versus 0% of controls (OR 281, P = 1.99 × 10⁻²¹). A phenome-wide association study in 9,438 unrelated European adults found the variant associated with major depressive disorder, insomnia, anxiety, and nicotine dependence. Of 48 CRY1Δ11 carriers with available psychiatric records, 46 (96%) displayed ADHD symptoms, and 64% had a history of recurrent depression compared with 10% of non-carriers.

Practical Actions

The circadian delay caused by CRY1Δ11 is mechanistically fixed — the protein is more active than normal — so the goal of treatment is to externally counteract the lengthened period rather than pharmacologically correct it. Two evidence-supported tools phase-advance the circadian clock: morning bright light and evening melatonin.

Morning bright light exposure (10,000 lux for 30 minutes immediately after waking) suppresses residual melatonin and signals the suprachiasmatic nucleus to advance the clock. Evening low-dose melatonin (0.5–3 mg taken 5–7 hours before desired sleep onset) directly phase-advances the melatonin rhythm. Combined bright light plus melatonin produces larger phase shifts than either alone99 Combined bright light plus melatonin produces larger phase shifts than either alone
Wilhelmsen-Langeland et al. J Biol Rhythms 2013, PMID 24132057. Because CRY1Δ11 carriers have a genuinely longer intrinsic period, they may need to sustain these interventions indefinitely rather than using them as a one-time correction.

Light avoidance in the evening is equally important. Evening light — especially blue-wavelength light from screens — delays the circadian clock by suppressing melatonin release. For carriers whose clock already runs late, evening light exposure amplifies the misalignment. Blue-light filtering glasses (amber lenses) from roughly 2 hours before desired bedtime reduce this phase-delaying input.

Homozygous carriers (GG) show no more severe clinical phenotype than heterozygous carriers in the published family data, consistent with the dominant gain-of-function mechanism reaching its ceiling with a single copy.

Interactions

CRY1Δ11 operates at the core of the CLOCK:BMAL1 → PER/CRY negative feedback loop. Other clock gene variants that affect this same loop can modulate the overall period length in concert with CRY1Δ11. The CRY2 gene encodes a paralogous cryptochrome; variants in CRY2 associated with earlier chronotype could theoretically counteract some period lengthening, though no published compound analysis exists for the CRY1Δ11 and CRY2 combination in humans.

The rs2287161 variant in CRY1 (a common intronic SNP) has been associated with major depressive disorder and depression risk in multiple populations, and may modulate baseline CRY1 expression levels independently of the CRY1Δ11 splice defect. Carriers of CRY1Δ11 who also carry rs2287161 risk alleles may have a higher burden of mood symptoms than CRY1Δ11 alone predicts.

The PERIOD genes PER1, PER2, and PER3 interact directly with CRY1 protein in the feedback loop. Common variants in PER3 (particularly the VNTR polymorphism rs57875989) affect sleep architecture and circadian preferences independently; their interaction with CRY1Δ11 has not been systematically studied but represents a plausible compounding pathway.

Genotype Interpretations

What each possible genotype means for this variant.

TT Standard Clock Normal

Standard CRY1 splicing — no circadian period lengthening from this variant

You carry two copies of the reference CRY1 allele, meaning your CRY1 protein is produced with its complete C-terminal tail intact. Your circadian clock period is not lengthened by this variant. About 99% of people share this genotype. Chronotype preferences (morning vs. evening) are still influenced by many other genetic and lifestyle factors, but this particular clock-period variant is not a contributor for you.

GT Night-Owl Carrier High Risk

One copy of CRY1Δ11 lengthens your circadian period by ~30 minutes, significantly delaying natural sleep timing

The CRY1Δ11 variant causes exon 11 of the CRY1 gene to be skipped during mRNA processing, producing a protein with a 24-amino-acid deletion in its C-terminal tail. This deletion paradoxically increases the protein's affinity for the CLOCK:BMAL1 transcription factor complex, lengthening the repression phase of the molecular oscillator. The free-running period of the proband in the founding study measured 24.52 hours (Patke et al. 2017). A 2021 observational study (Smieszek et al., Sci Rep) confirmed later wake times, sleep midpoints, and sleep-onset latency in 33 carriers compared to 34 matched wild-type controls, and found that the delay extends to bowel movement timing (~91 minutes later, p = 0.002), indicating a system-wide circadian shift. The variant also associates with ADHD, major depressive disorder, anxiety, and nicotine dependence in phenome-wide analyses (Onat et al. JCI 2020). No phenotypic difference between heterozygous and homozygous carriers was observed in the family data, consistent with a fully dominant mechanism.

GG Homozygous Night Owl High Risk

Two copies of CRY1Δ11 — same dominant circadian delay as one copy, but with complete absence of normal CRY1 splicing

The absence of any wild-type CRY1 splicing in homozygous carriers theoretically removes any residual normal-length protein from the oscillator. However, because the CRY1Δ11 effect is gain-of-function (enhanced inhibitory activity) rather than loss-of-function, adding a second copy does not compound the period extension beyond what one copy already achieves — the inhibitory activity ceiling is reached with a single dominant allele. This is consistent with the molecular data: mutant CRY1 already outcompetes wild-type CRY1 for CLOCK:BMAL1 binding. The 8 homozygous carriers in the founding study showed sleep phase delay indistinguishable from the 31 heterozygous carriers. All same management approaches apply.