PER3

Summary

PER3 (period circadian regulator 3, HGNC:8847) is a protein-coding gene on chromosome 1p36.23, encoding Period circadian protein homolog 3 (P56645). Originally described as a core component of the circadian clock.

This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene have been linked to sleep disorders. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8863 — RefSeq curated summary.

At a glance

• Gene–disease (curated): advanced sleep phase syndrome (Supportive, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 201 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 3
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_001377275

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8847
Approved symbol	PER3
Name	period circadian regulator 3
Location	1p36.23
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000049246
Ensembl biotype	protein_coding
OMIM	603427
Entrez	8863

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 15 protein_coding, 4 retained_intron

ENST00000361923, ENST00000377532, ENST00000377541, ENST00000463106, ENST00000473653, ENST00000494684, ENST00000602883, ENST00000613533, ENST00000614998, ENST00000893509, ENST00000893510, ENST00000893511, ENST00000893512, ENST00000917933, ENST00000961535, ENST00000961536, ENST00000961537, ENST00000961538, ENST00000961539

RefSeq mRNA: 7 — MANE Select: NM_001377275 NM_001289861, NM_001289862, NM_001289863, NM_001289864, NM_001377275, NM_001377276, NM_016831

CCDS: CCDS72695, CCDS76097, CCDS89

Canonical transcript exons

ENST00000377532 — 22 exons

Exon	Start	End
ENSE00000401688	7793957	7794008
ENSE00000401690	7801113	7801191
ENSE00000401693	7808893	7808998
ENSE00000401694	7809893	7810021
ENSE00000401696	7819285	7819420
ENSE00000401699	7826480	7826710
ENSE00000401718	7820467	7820640
ENSE00000737422	7836999	7837149
ENSE00000737423	7835762	7835945
ENSE00000737507	7827118	7827815
ENSE00000737659	7820115	7820239
ENSE00000737789	7810438	7810588
ENSE00000737793	7803047	7803153
ENSE00000738017	7785441	7785586
ENSE00000844090	7788045	7788246
ENSE00000844091	7798525	7798673
ENSE00000844094	7829834	7830161
ENSE00001173207	7784654	7785005
ENSE00001474227	7842672	7845177
ENSE00003590005	7786721	7786836
ENSE00003654652	7803692	7803848
ENSE00003921678	7784291	7784376

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 97.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.6562 / max 171.3050, expressed in 1585 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
440	5.1694	1317
445	1.1976	394
439	0.6592	270
446	0.5583	124
442	0.4957	262
441	0.4099	212
447	0.1662	65

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	97.02	gold quality
parietal pleura	UBERON:0002400	95.93	gold quality
cerebellar vermis	UBERON:0004720	95.85	gold quality
tibia	UBERON:0000979	95.20	gold quality
cerebellar cortex	UBERON:0002129	93.91	gold quality
cerebellar hemisphere	UBERON:0002245	93.87	gold quality
pleura	UBERON:0000977	93.75	gold quality
cerebellum	UBERON:0002037	93.56	gold quality
calcaneal tendon	UBERON:0003701	93.30	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.24	gold quality
visceral pleura	UBERON:0002401	92.53	gold quality
mucosa of stomach	UBERON:0001199	91.04	gold quality
esophagus squamous epithelium	UBERON:0006920	90.66	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	90.65	gold quality
upper leg skin	UBERON:0004262	90.24	gold quality
skin of hip	UBERON:0001554	90.02	gold quality
mucosa of paranasal sinus	UBERON:0005030	89.93	gold quality
adenohypophysis	UBERON:0002196	89.49	gold quality
corpus callosum	UBERON:0002336	88.98	gold quality
tendon	UBERON:0000043	88.96	gold quality
pigmented layer of retina	UBERON:0001782	88.64	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.49	gold quality
palpebral conjunctiva	UBERON:0001812	88.25	gold quality
spinal cord	UBERON:0002240	88.19	gold quality
seminal vesicle	UBERON:0000998	88.12	gold quality
upper arm skin	UBERON:0004263	87.94	gold quality
parotid gland	UBERON:0001831	87.69	gold quality
epithelium of esophagus	UBERON:0001976	87.53	gold quality
subthalamic nucleus	UBERON:0001906	87.43	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.33	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.83

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BMAL1, CLOCK, RAI1, SP1

miRNA regulators (miRDB)

103 targeting PER3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394

Literature-anchored findings (GeneRIF, showing 40)

• Polymorphism of period 3 (647 Val/Gly) is implicated in tendency of diurnal preference in seasonal depression as revealed by self-reported morningness-eveningness scores, with higher scores found in individuals with at least one glycine allele. (PMID:12655319)
• Circadian oscillations of Per1, Per2, and Per3 mRNA expression were observed in serum-stimulated normal human fibroblasts. (PMID:14712925)
• PER3 was cloned & sequenced. Homology and conserved motifs were determined. Transcripts of hPer3 underwent circadian oscillation. hPER1 increased between 3 and 12 h from an apparent molecular mass of 188 to 204 kDa. (PMID:14750904)
• disturbances in PER gene expression may result in disruption of the control of the normal circadian clock, thus benefiting the survival of cancer cells and promoting carcinogenesis (PMID:15790588)
• Data do not provide statistically significant evidence for association of PER3 with bipolar disorders(BPAD), but are suggestive of their involvement in BPAD. (PMID:16528748)
• Downregulated hPER3 expression in chronic myeloid leukemia is correlated with the inactivation of hPER3 by methylation (PMID:16999817)
• an association between the PER3 coding-region variable number tandem repeat and diurnal preference;4-repeat allele was significantly more frequent in evening types, and the 5-repeat allele more frequent in morning types (PMID:17309758)
• Homozygosity for the longer allele PER3(5/5) had a considerable effect on sleep, including several markers of sleep homeostasis and activity during wakefulness and REM sleep were all increased in PER3(5/5) compared to PER3(4/4) individuals. (PMID:17346965)
• Our results suggest that the 54-nucleotide repeat polymorphism of hPer3 significantly associates with heroin dependence at the allele frequency level and may be a potential risk factor for the development of heroin dependence. (PMID:17451453)
• This study demonstrated that rare genetic variants of hper3 are significantly associated to a number of mood disorders features, such as age of onset, response to SSRIs treatment, circadian mood oscillations and characteristics of temperament. (PMID:17512705)
• The expression level of PER3 was decreased in hepatocellular carcinoma. (PMID:18444243)
• The correlation between sleep timing and PER3 expression was stronger in individuals homozygous for the variant of the PER3 polymorphism that is associated with morningness. (PMID:18517031)
• This PER3 polymorphism differentially influences the effects of sleep deprivation on executive and non-executive function in the early morning. (PMID:18714788)
• A length polymorphism in the circadian clock gene Per3 influences age at onset of bipolar disorder. (PMID:18789374)
• PER3 polymorphism affects the sympathovagal balance in cardiac control in NREM sleep similar to the effect of sleep deprivation. (PMID:18835917)
• There was no significant age-related phase difference in PER1 or PER2 rhythm with respect to sleep timing; however, PER3 expression pattern was altered in the older subjects. (PMID:19013183)
• PER3 VNTR genotype may have a role in age-related differences in self-reported diurnal preference (PMID:19360490)
• amplitude of the PER3 rhythm at baseline is significantly reduced with age but this did not affect the response of the PER3 rhythm to light. (PMID:19444755)
• PER3 VNTR polymorphism is not associated with individual differences in neurobehavioral responses to partial sleep deprivation, although it was related to one marker of sleep homoeostatic response during PSD (PMID:19516903)
• The homozygosity for a variable-number (4 or 5) tandem-repeat polymorphism in the coding region of the clock gene PERIOD3 confers vulnerability to sleep loss and circadian misalignment through its effects on sleep homeostasis. (PMID:19553435)
• The association between sleep timing and the circadian rhythms of melatonin and PER3 RNA in leukocytes is stronger in PER3(5/5) than in PER3(4/4). (PMID:19716732)
• PER3 levels were correlated with fasting plasma glucose (beta = -.29, p < .05) and shift work (beta = .31, p < .05). (PMID:19861640)
• Per3 clock gene polymorphisms have also been associated with circadian disruption and with increased cancer risk. (PMID:19926609)
• The frequencies of the shorter allele (4 repeats) in the PER3 gene and the T allele in the CLOCK gene among Asians (0.86 and 0.84, respectively) were significantly higher than among Caucasians (0.69 and 0.71, respectively). (PMID:19967263)
• The T3111C (RS1801260) polymorphism of hClock gene is associated with schizophrenia, but it seems that the length polymorphism of 18 exon of hPer3 may not be associated with schizophrenia. (PMID:20364331)
• In mammals the circadian oscillation is driven by a negative feedback loop involving Per3 (PMID:20469812)
• Deletion of PER3 is directly related to tumor recurrence in patients with ER positive breast cancers treated with tamoxifen. Low expression of PER3 mRNA is associated with poor prognosis. (PMID:20625127)
• Per3 is a checkpoint protein that plays important roles in checkpoint activation, cell proliferation and apoptosis. (PMID:21070773)
• Data show the association remained significant between poor sleep quality and the Per3 rs228727 polymorphism in patients with bipolar disorder. (PMID:21176035)
• We showed a relationship between Per3 polymorphism and postpartum depressive onset in bipolar disorder. (PMID:21316201)
• Lean individuals exhibited significant (P < 0.05) temporal changes of core clock (PER1, PER2, PER3, CRY2, BMAL1, and DBP) and metabolic (REVERBalpha, RIP140, and PGC1alpha) genes. (PMID:21411511)
• PER1 and PER3 may modulate apoptotic reactions to cisplatin in gingival cancer cells (PMID:21459569)
• polymorphisms in UTS2 and PER3 may have roles in glucose homeostasis and diabetes (PMID:21559414)
• Failure to replicate previous research in relation to PERIOD3 and CLOCK concurs with previous research suggesting that the effects of these genes are small and may be related to population composition. (PMID:21714069)
• Decitabine can induce the expression of hPer3 gene and cells apoptosis in acute myeloid leukemia. (PMID:21729600)
• found no association between the PER3 clock gene VNTR polymorphism and chronotype, indicating that the proposed role of PER3 needs further clarification (PMID:21919721)
• The polymorphism in the clock gene PER3 may contribute to interindividual differences in sleep and circadian physiology in older people. (PMID:22169200)
• We provide first evidence that humans homozygous for the PER3 5/5 allele are particularly sensitive to blue-enriched light, as indexed by the suppression of endogenous melatonin and waking theta activity. (PMID:22188742)
• treatment with isoprenaline or dexamethasone induces circadian expression of hPer1, hPer2, hPer3, and hBMAL1 (PMID:22217103)
• Data suggest that the PER3 variable number tandem repeat specifically affects measures of sleep timing and may also modify the effects of sleep on health outcome measures. (PMID:22324552)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	per3	ENSDARG00000010519
mus_musculus	Per3	ENSMUSG00000028957
rattus_norvegicus	Per3	ENSRNOG00000018413
drosophila_melanogaster	per	FBGN0003068
caenorhabditis_elegans		WBGENE00018572

Paralogs (2): PER2 (ENSG00000132326), PER1 (ENSG00000179094)

Protein

Protein identifiers

Period circadian protein homolog 3 — P56645 (reviewed: P56645)

Alternative names: Cell growth-inhibiting gene 13 protein, Circadian clock protein PERIOD 3

All UniProt accessions (4): A0A087WV69, A2I2N5, P56645, Q8TAR6

UniProt curated annotations — full annotation on UniProt →

Function. Originally described as a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots ‘circa’ (about) and ‘diem’ (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for ’timegivers’). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5’-CACGTG-3’) within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1, NR1D2, RORA, RORB and RORG, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. Has a redundant role with the other PER proteins PER1 and PER2 and is not essential for the circadian rhythms maintenance. In contrast, plays an important role in sleep-wake timing and sleep homeostasis probably through the transcriptional regulation of sleep homeostasis-related genes, without influencing circadian parameters. Can bind heme.

Subunit / interactions. Homodimer. Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins. Interacts directly with PER1, PER2, CRY1, CRY2, and TIMELESS; interaction with CRY1 and CRY2 is weak and not rhythmic. Interacts with FBXW11 and BTRC.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylation by CSNK1E is weak and appears to require association with PER1 and translocation to the nucleus. Ubiquitinated.

Disease relevance. Advanced sleep phase syndrome, familial, 3 (FASPS3) [MIM:616882] An autosomal dominant disorder characterized by very early sleep onset and offset. Individuals are ‘morning larks’ with a 4 hours advance of the sleep, temperature and melatonin rhythms. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. The number of repeats of 18 amino acids in positions 966 to 1055 is polymorphic and varies among at least 2 different alleles. Alleles corresponding in size to a 4 (PER3.4) and 5 (PER3.5) repeats have been described. The sequence shown is that of allele PER3.5. In most populations around 10% of individuals are homozygous for the 5-repeat (PER3.5), whereas approximately 50% are homozygous for the 4-repeat (PER3.4). In some populations in Papua New Guinea the prevalence of the various genotypes appears to be reversed. These repeats and polymorphism are not present in non-primate mammals. Homozygosity for PER3.5 is more likely to show morning preference, whereas homozygosity for the PER3.4 associates with evening preferences. PER3.5 homozygous show vulnerability to sleep loss with a greater cognitive decline in response to total sleep deprivation.

Isoforms (2)

UniProt ID	Names	Canonical?
P56645-1	1	yes
P56645-2	2

RefSeq proteins (7): NP_001276790, NP_001276791, NP_001276792, NP_001276793, NP_001364204, NP_001364205, NP_058515 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR013655	PAS_fold_3	Domain
IPR022728	Period_circadian-like_C	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR048814	Per1-3_PAS-A	Domain
IPR050760	Period_circadian_regulator	Family
IPR057310	PER1-3_bHLH	Domain

Pfam: PF08447, PF12114, PF21353, PF23170

UniProt features (50 total): sequence variant 12, compositionally biased region 11, region of interest 7, repeat 5, short sequence motif 4, domain 3, modified residue 3, splice variant 3, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56645-F1	54.62	0.16

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 919, 994, 1053

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes
R-HSA-9931521	The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex
R-HSA-9931530	Phosphorylation and nuclear translocation of the CRY:PER:kinase complex
R-HSA-9932298	Degradation of CRY and PER proteins
R-HSA-9931512	Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters

MSigDB gene sets: 174 (showing top): GOBP_CIRCADIAN_RHYTHM, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_BEHAVIOR, GOBP_PHOTOPERIODISM, RIZ_ERYTHROID_DIFFERENTIATION_CCNE1, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_CIRCADIAN_REGULATION_OF_GENE_EXPRESSION, CHANDRAN_METASTASIS_DN, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, GOBP_REGULATION_OF_CIRCADIAN_RHYTHM, GOBP_REGULATION_OF_BEHAVIOR, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, MCLACHLAN_DENTAL_CARIES_DN, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM6, GOBP_PROTEIN_STABILIZATION

GO Biological Process (7): negative regulation of transcription by RNA polymerase II (GO:0000122), circadian regulation of gene expression (GO:0032922), entrainment of circadian clock by photoperiod (GO:0043153), regulation of circadian sleep/wake cycle, sleep (GO:0045187), protein stabilization (GO:0050821), circadian rhythm (GO:0007623), rhythmic process (GO:0048511)

GO Molecular Function (5): transcription cis-regulatory region binding (GO:0000976), transcription corepressor binding (GO:0001222), kinase binding (GO:0019900), ubiquitin protein ligase binding (GO:0031625), protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Circadian clock	5

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
circadian rhythm	1
regulation of gene expression	1
photoperiodism	1
entrainment of circadian clock	1
regulation of circadian sleep/wake cycle	1
circadian sleep/wake cycle, sleep	1
regulation of protein stability	1
rhythmic process	1
biological_process	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
transcription coregulator binding	1
enzyme binding	1
ubiquitin-like protein ligase binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

868 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PER3	CRY1	Q16526	991
PER3	CRY2	Q49AN0	984
PER3	NR1D1	P20393	972
PER3	NR1D2	Q14995	960
PER3	NFIL3	Q16649	955
PER3	RORB	Q92753	937
PER3	BHLHE41	Q9C0J9	928
PER3	RORA	P35397	922
PER3	BHLHE40	O14503	917
PER3	TIMELESS	Q9UNS1	893
PER3	CSNK1E	P49674	881
PER3	RORC	P51449	857
PER3	CSNK1D	P48730	831
PER3	CIART	Q8N365	714
PER3	TEF	Q10587	713

IntAct

11 interactions, top by confidence:

A	B	Type	Score
PER3	PER1	psi-mi:“MI:0914”(association)	0.500
PER3	PER1	psi-mi:“MI:0915”(physical association)	0.500
PER3	CHEK2	psi-mi:“MI:0915”(physical association)	0.500
PER3	CHEK2	psi-mi:“MI:0914”(association)	0.500
PER3	DHRS2	psi-mi:“MI:0915”(physical association)	0.400
PER3	CCDC88A	psi-mi:“MI:0914”(association)	0.350
CSNK1D		psi-mi:“MI:0914”(association)	0.350
yycF	PER3	psi-mi:“MI:0915”(physical association)	0.000
yscH	PER3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): CRY2 (Affinity Capture-MS), AVL9 (Affinity Capture-MS), CCDC88A (Affinity Capture-MS), MIB1 (Affinity Capture-MS), ANKRD36 (Affinity Capture-MS), FANCA (Affinity Capture-Luminescence), PER3 (Affinity Capture-Western), PER2 (Affinity Capture-Western), PER3 (Affinity Capture-Western), DHRS2 (Proximity Label-MS), EMB (Affinity Capture-MS), FAT3 (Affinity Capture-MS), PER1 (Affinity Capture-MS), CLUH (Affinity Capture-MS), SCGB1D2 (Affinity Capture-MS)

ESM2 similar proteins: A0MLS5, G5EGD2, O00327, O02219, O02747, O02748, O15945, O35800, O44712, O88529, P27540, P30561, P35869, P41738, P41739, P53762, P56645, P79832, P97481, Q0PGG7, Q16665, Q17062, Q2VPD4, Q309Z6, Q5R4T2, Q61221, Q61324, Q6YGZ5, Q78E60, Q8K3T2, Q8QGQ7, Q8QGQ8, Q8R4S2, Q8R4S4, Q8R4S5, Q8R4S6, Q8R4S7, Q8WYA1, Q91YA9, Q95LD9

Diamond homologs: O15055, O15534, O35973, O54943, O70361, P56645, Q8CHI5, Q8CJE2, Q8K3T2, Q8K3T3, Q8QGQ8, Q9Z301, P07663, Q03297, Q03353, Q03354, Q03355, Q24767, Q2VPD4, P12348, P97460, O08785, O15516, O61735, Q5RAK8, Q5ZQU2, Q6YGZ4, Q8QGQ6, Q91YA8, Q91YB0, Q91YB2, Q99743, Q9WVS9, Q9Y6Q9, O02748, P12349, P27540, P41739, Q25478, Q25637

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
RAI1	“up-regulates quantity by expression”	PER3	“transcriptional regulation”
CSNK1E	“down-regulates quantity by destabilization”	PER3	phosphorylation
CSNK1D	“down-regulates quantity by destabilization”	PER3	phosphorylation
CSNK1E	“down-regulates activity”	PER3	phosphorylation
ARNTL	“up-regulates quantity by expression”	PER3	“transcriptional regulation”
CLOCK	“up-regulates quantity by expression”	PER3	“transcriptional regulation”
CLOCK/BMAL1	“up-regulates quantity by expression”	PER3	“transcriptional regulation”

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — LUAD.

Clinical variants and AI predictions

ClinVar

201 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	127
Likely benign	31
Benign	9

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
3779970	NM_001377275.1(PER3):c.3399-80_3399-77del	Pathogenic
1098359	NM_001377275.1(PER3):c.1998dup (p.Met667fs)	Likely pathogenic
623670	NM_001377275.1(PER3):c.749_753del (p.Pro250fs)	Likely pathogenic

SpliceAI

4199 predictions. Top by Δscore:

Variant	Effect	Δscore
1:7784890:G:T	donor_gain	1.0000
1:7785436:TCCA:T	acceptor_loss	1.0000
1:7785437:CCA:C	acceptor_loss	1.0000
1:7785438:CA:C	acceptor_loss	1.0000
1:7785439:A:AG	acceptor_gain	1.0000
1:7785439:AGT:A	acceptor_gain	1.0000
1:7785440:G:GT	acceptor_gain	1.0000
1:7785440:GT:G	acceptor_gain	1.0000
1:7785440:GTG:G	acceptor_gain	1.0000
1:7785440:GTGA:G	acceptor_gain	1.0000
1:7787196:A:AG	acceptor_gain	1.0000
1:7787197:G:GG	acceptor_gain	1.0000
1:7798523:A:AG	acceptor_gain	1.0000
1:7798523:AGT:A	acceptor_gain	1.0000
1:7798524:G:GT	acceptor_gain	1.0000
1:7798524:GT:G	acceptor_gain	1.0000
1:7798524:GTG:G	acceptor_gain	1.0000
1:7798524:GTGGA:G	acceptor_gain	1.0000
1:7801110:TAG:T	acceptor_loss	1.0000
1:7801111:A:AG	acceptor_gain	1.0000
1:7801111:A:G	acceptor_loss	1.0000
1:7801112:G:A	acceptor_loss	1.0000
1:7801112:G:GT	acceptor_gain	1.0000
1:7801112:GC:G	acceptor_gain	1.0000
1:7801112:GCT:G	acceptor_gain	1.0000
1:7801112:GCTC:G	acceptor_gain	1.0000
1:7801112:GCTCC:G	acceptor_gain	1.0000
1:7801187:GAAAA:G	donor_gain	1.0000
1:7801188:AAAA:A	donor_gain	1.0000
1:7801189:AAA:A	donor_gain	1.0000

AlphaMissense

7928 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:7803781:T:A	W356R	0.996
1:7803781:T:C	W356R	0.996
1:7803787:A:C	S358R	0.989
1:7803789:C:A	S358R	0.989
1:7803789:C:G	S358R	0.989
1:7803790:T:C	F359L	0.989
1:7803792:T:A	F359L	0.989
1:7803792:T:G	F359L	0.989
1:7820120:T:C	L547P	0.989
1:7801143:T:C	F274S	0.988
1:7803833:G:C	R373P	0.986
1:7785551:T:C	L80P	0.983
1:7785560:C:A	A83D	0.982
1:7803784:T:C	S357P	0.980
1:7803835:C:G	H374D	0.980
1:7801142:T:C	F274L	0.979
1:7801144:C:A	F274L	0.979
1:7801144:C:G	F274L	0.979
1:7785551:T:A	L80H	0.978
1:7803783:G:C	W356C	0.977
1:7803783:G:T	W356C	0.977
1:7820148:A:C	K556N	0.977
1:7820148:A:T	K556N	0.977
1:7803820:T:C	F369L	0.976
1:7803822:C:A	F369L	0.976
1:7803822:C:G	F369L	0.976
1:7803830:G:A	G372D	0.976
1:7819414:T:A	V543D	0.976
1:7808915:T:C	F386L	0.972
1:7808917:T:A	F386L	0.972

dbSNP variants (sampled 300 via entrez): RS1000030340 (1:7802955 C>G), RS1000092711 (1:7809072 C>T), RS1000140830 (1:7838513 AT>A), RS1000173403 (1:7810955 C>A), RS1000187417 (1:7796468 A>C,G), RS1000206182 (1:7810645 G>A), RS1000266401 (1:7839664 G>C), RS1000282033 (1:7791401 G>A), RS1000312378 (1:7792970 A>T), RS1000318332 (1:7844841 T>C), RS1000361633 (1:7844893 T>G), RS1000370895 (1:7794289 T>G), RS1000443678 (1:7838792 A>C), RS1000484374 (1:7827957 G>A,T), RS1000512604 (1:7809545 A>C)

Disease associations

OMIM: gene MIM:603427 | disease phenotypes: MIM:616882, MIM:236270, MIM:604348

GenCC curated gene-disease

Disease	Classification	Inheritance
advanced sleep phase syndrome	Supportive	Autosomal dominant

Mondo (3): advanced sleep phase syndrome 3 (MONDO:0014814), methylcobalamin deficiency type cblE (MONDO:0009354), advanced sleep phase syndrome (MONDO:0015609)

Orphanet (3): Familial advanced sleep-phase syndrome (Orphanet:164736), Methylcobalamin deficiency type cblE (Orphanet:2169), Homocystinuria without methylmalonic aciduria (Orphanet:622)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000716	Depression
HP:0031873	Early chronotype

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST003429_37	Morning vs. evening chronotype	2.000000e-08
GCST004131_79	Inflammatory bowel disease	1.000000e-12
GCST004132_92	Crohn’s disease	3.000000e-06
GCST004133_62	Ulcerative colitis	4.000000e-09
GCST007565_96	Morning person	5.000000e-41
GCST007576_294	Chronotype	5.000000e-41
GCST007576_302	Chronotype	3.000000e-26
GCST007576_303	Chronotype	7.000000e-40

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565510	Homocystinuria-Megaloblastic Anemia due to Defect in Cobalamin Metabolism, CblE Complementation Type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs228642	PER3		0.00	0
rs228666	PER3		0.00	0
rs228697	PER3		0.00	0
rs228729	PER3		0.00	0
rs2640909	PER3		0.00	0
rs2859388	PER3		0.00	0

CTD chemical–gene interactions

61 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	5
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
ochratoxin A	increases expression	1
potassium chromate(VI)	decreases expression	1
ferrous chloride	increases expression	1
pentanal	decreases expression	1
phenethyl isothiocyanate	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
perfluorohexanesulfonic acid	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
eprenetapopt	affects expression, affects reaction	1
jinfukang	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Vorinostat	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Aldehydes	decreases expression	1

Clinical trials (associated diseases)

4 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03956745	Not specified	TERMINATED	Biomarkers for Circadian Timing in Healthy Adults
NCT03980340	Not specified	TERMINATED	Breath Biomarkers for Sleep Loss and Circadian Timing
NCT04690504	Not specified	COMPLETED	Validation of Circadian Biomarkers in Patients With Sleep Disorders
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns