PER2

Summary

PER2 (period circadian regulator 2, HGNC:8846) is a protein-coding gene on chromosome 2q37.3, encoding Period circadian protein homolog 2 (O15055). Transcriptional repressor which forms 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 may increase the risk of getting certain cancers and have been linked to sleep disorders.

Source: NCBI Gene 8864 — RefSeq curated summary.

At a glance

• Gene–disease (curated): advanced sleep phase syndrome (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 252 total — 2 pathogenic
• GTEx eGene: eQTL in 5 tissues, sQTL in 9 (q < 0.05)
• Phenotypes (HPO): 4
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.67 (unconstrained)
• MANE Select transcript: NM_022817
• Notable: 252 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8846
Approved symbol	PER2
Name	period circadian regulator 2
Location	2q37.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0347
Ensembl gene	ENSG00000132326
Ensembl biotype	protein_coding
OMIM	603426
Entrez	8864

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

MANE Select: ENST00000254657

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 4: 1, TSL 5: 1

ENST00000254657, ENST00000355768, ENST00000431832, ENST00000491417, ENST00000707129, ENST00000707130, ENST00001004721, ENST00001004722, ENST00001108669

RefSeq mRNA: 1 — MANE Select: NM_022817 NM_022817

CCDS: CCDS2528

Canonical transcript exons

ENST00000254657 — 23 exons

Exon	Start	End
ENSE00001907929	238288349	238288610
ENSE00002203304	238268923	238268974
ENSE00002234281	238268056	238268198
ENSE00002235351	238265512	238265590
ENSE00002244406	238277707	238277955
ENSE00002263097	238275743	238275897
ENSE00002266522	238271312	238271513
ENSE00002287732	238277131	238277193
ENSE00002293302	238273070	238273191
ENSE00002316057	238262952	238263058
ENSE00003459412	238249062	238249212
ENSE00003477609	238258497	238258644
ENSE00003483172	238256922	238257086
ENSE00003489025	238259969	238260053
ENSE00003520505	238258276	238258400
ENSE00003552378	238250551	238250743
ENSE00003562531	238252912	238253702
ENSE00003593814	238251599	238251761
ENSE00003595645	238260828	238260953
ENSE00003596173	238261729	238261837
ENSE00003607402	238262191	238262344
ENSE00003643513	238244044	238246524
ENSE00003689231	238255657	238255911

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 97.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.5479 / max 183.3407, expressed in 1606 samples.

Highest expression (Bgee): oocyte, mucosa of paranasal sinus, secondary oocyte, bronchial epithelial cell, epithelium of bronchus.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PER2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 5 tissues and its splicing (sQTL) in 9 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

14 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Muscularis	sqtl	1.1e-11	-0.83	2:238285197:A:G
Thyroid	sqtl	7.0e-05	-0.42	2:238267745:A:G
Artery Tibial	eqtl	2.6e-03	-0.15	2:238944862:A:G
Prostate	sqtl	3.5e-03	-1.07	2:238257165:C:A
Colon Sigmoid	sqtl	4.3e-03	-0.61	2:238271002:C:T
Brain Frontal Cortex BA9	eqtl	6.0e-03	-1.13	2:237665301:ATTAC:A
Minor Salivary Gland	sqtl	8.1e-03	-3.17	2:238645226:A:G
Nerve Tibial	eqtl	1.2e-02	+0.46	2:237584109:G:A
Muscle Skeletal	eqtl	1.3e-02	+0.25	2:237786731:G:A
Colon Transverse	eqtl	1.8e-02	-0.72	2:238536383:G:T
Esophagus Mucosa	sqtl	1.9e-02	-0.40	2:237519684:T:C
Artery Tibial	sqtl	2.4e-02	-0.98	2:238596420:A:G
Lung	sqtl	3.2e-02	-1.55	2:238796682:C:T
Muscle Skeletal	sqtl	3.6e-02	-1.04	2:237717474:C:G

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
34767	7.1173	1535
34766	0.6574	332
34765	0.3356	177
34764	0.2030	98
34763	0.1429	59
34768	0.0917	41

Top tissues by expression

showing 100 of 300 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	97.35	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.91	gold quality
secondary oocyte	CL:0000655	95.69	gold quality
bronchial epithelial cell	CL:0002328	95.18	gold quality
epithelium of bronchus	UBERON:0002031	94.97	gold quality
bronchus	UBERON:0002185	94.71	gold quality
palpebral conjunctiva	UBERON:0001812	94.32	gold quality
nasal cavity epithelium	UBERON:0005384	94.07	gold quality
cauda epididymis	UBERON:0004360	92.77	gold quality
urethra	UBERON:0000057	92.20	gold quality
caput epididymis	UBERON:0004358	91.99	gold quality
upper leg skin	UBERON:0004262	91.87	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.46	gold quality
skin of hip	UBERON:0001554	91.42	gold quality
mammary duct	UBERON:0001765	91.25	gold quality
epithelium of mammary gland	UBERON:0003244	91.24	gold quality
nasal cavity mucosa	UBERON:0001826	91.20	gold quality
adult organism	UBERON:0007023	91.15	gold quality
gingiva	UBERON:0001828	91.08	gold quality
hair follicle	UBERON:0002073	90.76	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.56	gold quality
epithelium of nasopharynx	UBERON:0001951	90.50	gold quality
oviduct epithelium	UBERON:0004804	90.42	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.19	gold quality
tibia	UBERON:0000979	90.16	gold quality
gingival epithelium	UBERON:0001949	90.03	gold quality
blood vessel layer	UBERON:0004797	89.93	gold quality
corpus epididymis	UBERON:0004359	89.87	gold quality
seminal vesicle	UBERON:0000998	89.78	gold quality
saphenous vein	UBERON:0007318	89.77	gold quality
parietal pleura	UBERON:0002400	89.35	gold quality
eye	UBERON:0000970	89.16	gold quality
cervix squamous epithelium	UBERON:0006922	89.08	gold quality
parotid gland	UBERON:0001831	88.95	gold quality
pleura	UBERON:0000977	88.82	gold quality
oral cavity	UBERON:0000167	88.59	gold quality
colonic mucosa	UBERON:0000317	88.51	gold quality
tongue squamous epithelium	UBERON:0006919	88.16	silver quality
germinal epithelium of ovary	UBERON:0001304	88.07	gold quality
vastus lateralis	UBERON:0001379	87.95	gold quality
synovial joint	UBERON:0002217	87.73	gold quality
mammary gland	UBERON:0001911	87.63	gold quality
mucosa of urinary bladder	UBERON:0001259	87.55	gold quality
thoracic mammary gland	UBERON:0005200	87.54	gold quality
visceral pleura	UBERON:0002401	87.48	gold quality
tibialis anterior	UBERON:0001385	87.30	gold quality
trachea	UBERON:0003126	87.15	gold quality
penis	UBERON:0000989	87.13	gold quality
quadriceps femoris	UBERON:0001377	87.10	gold quality
squamous epithelium	UBERON:0006914	86.95	gold quality
pharyngeal mucosa	UBERON:0000355	86.85	gold quality
cranial nerve II	UBERON:0000941	86.42	gold quality
nipple	UBERON:0002030	86.41	gold quality
pancreatic ductal cell	CL:0002079	86.35	gold quality
ileal mucosa	UBERON:0000331	86.10	gold quality
mammalian vulva	UBERON:0000997	86.08	gold quality
fallopian tube	UBERON:0003889	85.97	gold quality
jejunal mucosa	UBERON:0000399	85.95	gold quality
calcaneal tendon	UBERON:0003701	85.93	gold quality
layer of synovial tissue	UBERON:0007616	85.87	gold quality
mucosa of stomach	UBERON:0001199	85.85	gold quality
superior surface of tongue	UBERON:0007371	85.70	gold quality
superficial temporal artery	UBERON:0001614	85.58	gold quality
cervix epithelium	UBERON:0004801	85.38	gold quality
biceps brachii	UBERON:0001507	85.25	gold quality
sural nerve	UBERON:0015488	85.13	gold quality
zone of skin	UBERON:0000014	85.07	gold quality
epithelium of esophagus	UBERON:0001976	84.91	gold quality
skin of abdomen	UBERON:0001416	84.77	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.76	gold quality
skeletal muscle tissue	UBERON:0001134	84.42	gold quality
skin of leg	UBERON:0001511	84.34	gold quality
esophagus squamous epithelium	UBERON:0006920	84.31	gold quality
mouth mucosa	UBERON:0003729	84.28	gold quality
tendon	UBERON:0000043	83.95	gold quality
saliva-secreting gland	UBERON:0001044	83.95	gold quality
deltoid	UBERON:0001476	83.88	silver quality
vena cava	UBERON:0004087	83.81	gold quality
muscle tissue	UBERON:0002385	83.68	gold quality
lower lobe of lung	UBERON:0008949	83.67	gold quality
right uterine tube	UBERON:0001302	83.56	gold quality
tongue	UBERON:0001723	83.53	gold quality
minor salivary gland	UBERON:0001830	83.51	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	83.16	gold quality
tonsil	UBERON:0002372	82.97	gold quality
uterine cervix	UBERON:0000002	82.88	gold quality
gall bladder	UBERON:0002110	82.83	gold quality
body of stomach	UBERON:0001161	82.63	gold quality
endometrium	UBERON:0001295	82.50	gold quality
epithelial cell of pancreas	CL:0000083	82.37	gold quality
cardiac muscle of right atrium	UBERON:0003379	82.33	gold quality
buccal mucosa cell	CL:0002336	82.21	gold quality
muscle organ	UBERON:0001630	82.19	gold quality
skeletal muscle organ	UBERON:0014892	82.19	gold quality
Brodmann (1909) area 23	UBERON:0013554	82.07	gold quality
stomach	UBERON:0000945	82.04	gold quality
Brodmann (1909) area 46	UBERON:0006483	82.01	gold quality
urinary bladder	UBERON:0001255	81.90	gold quality
prostate gland	UBERON:0002367	81.76	gold quality
hindlimb stylopod muscle	UBERON:0004252	81.14	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-81608	no	726.94
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Cerebellum	tissue	20.4	medium
Caudate putamen	tissue	16.5
Hippocampus	tissue	13.8	medium
Pancreas	tissue	13.7	medium
Breast	tissue	13.5	medium
Frontal cortex	tissue	13.4
Nucleus accumbens	tissue	13.3
Esophagus	tissue	12.9	medium
Stomach 1	tissue	12.7	medium
Liver	tissue	11.7	low
Adipose tissue	tissue	11.6	low
Gallbladder	tissue	11.5	medium
Cervix	tissue	11.3	high
Salivary gland	tissue	11.3	medium
Testis	tissue	11.1	high
Locus coeruleus	tissue	11.0
Skeletal muscle	tissue	10.7	medium
Cerebral cortex	tissue	10.2	medium
Choroid plexus	tissue	10.2
Occipital cortex	tissue	10.2
Postcentral gyrus	tissue	9.9
Endometrium 1	tissue	9.7	medium
Prefrontal cortex	tissue	9.6
Somatosensory cortex	tissue	9.6
Hippocampal formation	tissue	9.5
Entorhinal cortex	tissue	9.5
Motor cortex	tissue	9.1
Retrosplenial and cingulate cortex	tissue	9.1
Retrosplenial cortex	tissue	9.0
Insular cortex	tissue	8.9
Temporal cortex	tissue	8.8
Pituitary gland	tissue	8.7
Seminal vesicle	tissue	8.4	medium
Prostate	tissue	8.4	low
Thyroid gland	tissue	8.3	high
Urinary bladder	tissue	8.1	medium
Bone marrow	tissue	8.0	medium
Vagina	tissue	7.6	medium
Small intestine	tissue	7.5	medium
Olfactory bulb	tissue	7.5
Tongue	tissue	7.2
Basal ganglia	tissue	7.2	medium
Fallopian tube	tissue	7.2	medium
Colon	tissue	7.1	medium
Putamen	tissue	6.9
Lung	tissue	6.8	medium
Ovary	tissue	6.7	medium
Spinal cord	tissue	6.4
Amygdala	tissue	6.2
Ventral forebrain	tissue	6.2
Thalamus	tissue	6.1
Rectum	tissue	5.9	high
Superior colliculi	tissue	5.9
Tonsil	tissue	5.9	medium
Septum	tissue	5.9
Skin 1	tissue	5.8	medium
Hypothalamus	tissue	5.8
Heart muscle	tissue	5.4	medium
Pons	tissue	5.4
Epididymis	tissue	5.4	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Vermis (20.0), Flocculonodular lobe (19.9), Cerebellar cortex (17.5), Periaquaductal grey, lateral (17.3), Cervical spinal cord, central gray (17.0).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets:

Target	Regulation
SERPINE1
SNAI2	Repression
TWIST1	Repression

Upstream regulators (CollecTRI, top): ATF2, ATF4, BHLHE40, BMAL1, BMAL2, CEBPA, CEBPE, CLOCK, CREB1, DBP, EGR1, ELK1, FOXC1, GMEB1, HLF, HR, JARID2, KDM5A, MBD2, NFIL3, NPAS2, NR3C1, RAI1, TEF, TP53

miRNA regulators (miRDB)

Targeting PER2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 118 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
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-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819

Functional genomics

gnomAD constraint: pLI 6.83e-08, LOEUF 0.67, missense Z 1.28 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000254657 — one region, missense o/e 0.93.

Literature-anchored findings (GeneRIF, showing 40)

• The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. (PMID:12372299)
• Polymorphism of the PER2 casein kinase I epsilon binding region is unlikely to play an important role in the development of bipolar disorder. (PMID:12565145)
• Circadian oscillations of Per1, Per2, and Per3 mRNA expression were observed in serum-stimulated normal human fibroblasts. (PMID:14712925)
• Transcripts of hPer2 underwent circadian oscillation. The mRNA levels reached a maximum at 4 h and minimal levels at 12 h. (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)
• Per2 levels were reduced in lymphoma cell lines and in acute myeloid leukemia (AML) patient samples (PMID:15985538)
• per2 gene is associated with diurnal sleep preference. (PMID:16120104)
• Point mutations in the prion protein, period 2, and the prepro-hypocretin/orexin gene have been found as the cause of a few sleep disorders. (PMID:16338760)
• Evening exposure to blue light stimulates the expression of the clock gene PER2. (PMID:16519674)
• Phosphorylation at Serine 662 leads to increased PER2 transcription and suggest that phosphorylation at another site leads to PER2 degradation. (PMID:17218255)
• We have examined the circadian expression of clock genes in human leukocytes and found that Per2 mRNA showed weak rhythm. (PMID:17274950)
• A clear circadian rhythm was shown for hPer1, hPer2, and hCry2 expression in CD34(+) cells and for hPer1 in the whole bone marrow, with maxima from early morning to midday. (PMID:17440215)
• variations associated with seasonal affective disorder (PMID:17457720)
• Per2, a core clock gene, links the circadian cycle to the ERalpha signaling network. (PMID:17599055)
• a role for both Per1 and Per2 in normal breast function and show for the first time that deregulation of the circadian clock may be an important factor in the development of familial breast cancer (PMID:17971899)
• The regulators of clock-controlled transcription PER2, CRY1 and CRY2 differ in their capacity to interact with each single component of the BMAL1-CLOCK heterodimer and, in the case of BMAL1, also in their interaction sites. (PMID:18430226)
• The expression level of PER2 was decreased in hepatocellular carcinoma. (PMID:18444243)
• The data support a model where heme-mediated oxidation triggers hPer2 degradation, thus controlling heterodimerization and ultimately gene transcription. (PMID:18505821)
• Individual PER3 rhythms correlated significantly with sleep-wake timing and the timing of melatonin and cortisol, but those of PER2 and BMAL1 did not reach significance. (PMID:18517031)
• These data support the hypothesis that circadian clock genes can control the cell cycle and cell survival signaling, and emphasize a central role of CK1epsilon and PERIOD2 in linking these systems. (PMID:18518968)
• PER2 might have been influenced by positive selection, and offers preliminary insights into the evolution of this functional class of genes (PMID:18575464)
• 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)
• These findings suggest that disruption of the peripheral intestinal circadian clock may be intimately involved in beta-catenin induced intestinal epithelial neoplastic transformation in both mouse and man. (PMID:19106159)
• We propose a new concept of how PER2 phosphorylation and stabilization can set the clock speed in opposite directions, dependent on the phase of action. (PMID:19299560)
• differential expression and prognostic significance of the circadian genes CRY1 and PER2 in chronic lymphocytic leukemia (PMID:19500131)
• PER2 is inhibited by BMAL2-CLOCK, which reemphasizes its negative role and a positive role of BMAL2 in circadian transcription (PMID:19605937)
• genetic variation in PER2 is associated with depression vulnerability a Swedish population-based sample (PMID:19693801)
• Evidence suggests metabolic processes feed back into the circadian clock, affecting clock and per2 gene expression and timing of behaviour. (PMID:19714310)
• significant reduction in PER2 expression in oral mucosa with aging in the morning, noon, and afternoon (PMID:19916842)
• levels of Per2 were reduced in lymphoma and acute myeloid leukemia patient samples (PMID:19926610)
• displayed a significant anti-tumor effect through cell cycle arrest and apoptosis induction in K562 leukemia cells (PMID:19957060)
• PER2 gene variation is associated with alcohol consumption in interaction with sleep problems among Swedish adolescent boys (PMID:20187847)
• The expression levels of Per2 in glioma cells were significantly different from the surrounding non-glioma cells. The difference in the expression rate of Per2 in high-grade (grade III and IV) and low-grade (grade 1 and II) gliomas was insignificant. (PMID:20481271)
• PER2 is implicated in attrition in weight-loss treatment and may modulate eating-behavior-related phenotypes. (PMID:20497782)
• Per2 C111G SNPs do not influence circadian rhythmicity in healthy Italian population. (PMID:20886252)
• rs934945 of PER2 may be associated with diurnal preference in a Korean healthy population (PMID:20931356)
• Data found that the pool of Ser-662-phosphorylated PER2 proteins was more stable than the pool of total PER2 molecules, implying that the FASPS phosphorylation cluster antagonizes PER2 degradation. (PMID:21324900)
• reduced expression of the Per2 gene may be a predictor of outcomes in patients with colorectal cancer. (PMID:21380491)
• 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)
• This study demonstrated a novel mechanism for alcohol-induced intestinal hyperpermeability through stimulation of intestinal circadian Per2 and CLOCK gene expression. (PMID:21463335)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	per2	ENSDARG00000034503
mus_musculus	Per2	ENSMUSG00000055866
rattus_norvegicus	Per2	ENSRNOG00000020254
drosophila_melanogaster	per	FBGN0003068
caenorhabditis_elegans		WBGENE00018572

Paralogs (2): PER3 (ENSG00000049246), PER1 (ENSG00000179094)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1195265) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 46 distinct phenotype terms.

Mouse phenotype (MP)	Records
shortened circadian behavior period	3
arrhythmic circadian behavior persistence	3
salivary gland epithelial hyperplasia	1
abnormal body weight	1
increased body weight	1
abnormal retina morphology	1
pup cannibalization	1
abnormal food preference	1
abnormal sleep pattern	1
abnormal blood vessel morphology	1
increased mortality induced by gamma-irradiation	1
reduced female fertility	1
decreased litter size	1
abnormal coat/hair pigmentation	1
premature death	1
abnormal bone marrow cell morphology/development	1
abnormal male preputial gland morphology	1
abnormal retina vasculature morphology	1
abnormal bone mineralization	1
increased circulating alkaline phosphatase level	1
decreased cellular sensitivity to gamma-irradiation	1
abnormal nervous system morphology	1
increased incidence of tumors by ionizing radiation induction	1
increased hematopoietic stem cell number	1
abnormal brain wave pattern	1

+21 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Gallus gallus	Q8QGQ8	57.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
IFT54	protein-coding	26146
ASB1	protein-coding	51665
HES6	protein-coding	55502
LINC02610	ncRNA	151174
ILKAP	protein-coding	80895

Protein

Protein identifiers

Period circadian protein homolog 2 — O15055 (reviewed: O15055)

Alternative names: Circadian clock protein PERIOD 2

All UniProt accessions (2): E9PD89, O15055

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor which forms 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 syndrome 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 NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. PER1 and PER2 proteins transport CRY1 and CRY2 into the nucleus with appropriate circadian timing, but also contribute directly to repression of clock-controlled target genes through interaction with several classes of RNA-binding proteins, helicases and others transcriptional repressors. PER appears to regulate circadian control of transcription by at least three different modes. First, interacts directly with the CLOCK-BMAL1 at the tail end of the nascent transcript peak to recruit complexes containing the SIN3-HDAC that remodel chromatin to repress transcription. Second, brings H3K9 methyltransferases such as SUV39H1 and SUV39H2 to the E-box elements of the circadian target genes, like PER2 itself or PER1. The recruitment of each repressive modifier to the DNA seems to be very precisely temporally orchestrated by the large PER complex, the deacetylases acting before than the methyltransferases. Additionally, large PER complexes are also recruited to the target genes 3’ termination site through interactions with RNA-binding proteins and helicases that may play a role in transcription termination to regulate transcription independently of CLOCK-BMAL1 interactions. Recruitment of large PER complexes to the elongating polymerase at PER and CRY termination sites inhibited SETX action, impeding RNA polymerase II release and thereby repressing transcriptional reinitiation. May propagate clock information to metabolic pathways via the interaction with nuclear receptors. Coactivator of PPARA and corepressor of NR1D1, binds rhythmically at the promoter of nuclear receptors target genes like BMAL1 or G6PC1. Directly and specifically represses PPARG proadipogenic activity by blocking PPARG recruitment to target promoters and thereby inhibiting transcriptional activation. Required for fatty acid and lipid metabolism, is involved as well in the regulation of circulating insulin levels. Plays an important role in the maintenance of cardiovascular functions through the regulation of NO and vasodilatatory prostaglandins production in aortas. Controls circadian glutamate uptake in synaptic vesicles through the regulation of VGLUT1 expression. May also be involved in the regulation of inflammatory processes. Represses the CLOCK-BMAL1 induced transcription of BHLHE40/DEC1 and ATF4. Negatively regulates the formation of the TIMELESS-CRY1 complex by competing with TIMELESS for binding to CRY1.

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 with CLOCK-BMAL1 (off DNA). Interacts with BMAL2. Interacts directly with PER1 and PER3, and through a C-terminal domain, with CRY1 and CRY2. Interacts (via PAS 2 domain) with TIMELESS. Interacts with NFIL3. Different large complexes have been identified with different repressive functions. The core of PER complexes is composed of at least PER1, PER2, PER3, CRY1, CRY2, CSNK1D and/or CSNK1E. The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (active). The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A. The large PER complex involved in the histone methylation is composed of at least PER2, CBX3, TRIM28, SUV39H1 and/or SUV39H2; CBX3 mediates the formation of the complex. Interacts with SETX; the interaction inhibits termination of circadian target genes. Interacts with the nuclear receptors HNF4A, NR1D1, NR4A2, RORA, PPARA, PPARG and THRA; the interaction with at least PPARG is ligand dependent. Interacts with PML. Interacts (phosphorylated) with BTRC and FBXW11; the interactions trigger proteasomal degradation. Interacts with NONO and SFPQ. Interacts with CAVIN3. Interacts with MAGEL2. Interacts with MAP1LC3B. Interacts with HNF4A.

Subcellular location. Nucleus. Cytoplasm. Perinuclear region Nucleus. Nucleolus.

Tissue specificity. Widely expressed. Found in heart, brain, placenta, lung, liver, skeleatal muscle, kidney and pancreas. High levels in skeletal muscle and pancreas. Low levels in lung. Isoform 2 is expressed in keratinocytes (at protein level).

Post-translational modifications. Acetylated. Deacetylated by SIRT1, resulting in decreased protein stability. Deacetylated by SIRT6, preventing its degradation by the proteasome, resulting in increased protein stability. Phosphorylated by CSNK1E and CSNK1D. Phosphorylation results in PER2 protein degradation. May be dephosphorylated by PP1. Ubiquitinated, leading to its proteasomal degradation. Ubiquitination may be inhibited by CRY1.

Disease relevance. Advanced sleep phase syndrome, familial, 1 (FASPS1) [MIM:604348] 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.

Induction. Oscillates diurnally. Rhythmic levels are critical for the generation of circadian rhythms in central as well as peripheral clocks. Targeted degradation of PER and CRY proteins enables the reactivation of CLOCK-BMAL1, thus initiating a new circadian transcriptional cycle with an intrinsic period of 24 hours.

Isoforms (2)

UniProt ID	Names	Canonical?
O15055-1	1	yes
O15055-2	2, PER2S

RefSeq proteins (1): NP_073728* (*=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 (61 total): modified residue 13, region of interest 12, compositionally biased region 8, sequence variant 7, short sequence motif 6, helix 6, domain 3, splice variant 2, turn 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
8D7O	Human Casein kinase 1 delta in complex with phosphorylated human PERIOD2 FASP peptide	X-RAY DIFFRACTION	1.65
8D7N	Human Casein kinase 1 delta in complex with phosphorylated human PERIOD2 FASP peptide	X-RAY DIFFRACTION	1.66
8D7M	Human Casein kinase 1 delta in complex with phosphorylated human PERIOD2 FASP peptide	X-RAY DIFFRACTION	2.25
6OF7	Crystal structure of the CRY1-PER2 complex	X-RAY DIFFRACTION	3.11

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15055-F1	53.96	0.16

Human Protein Atlas

Protein class: Predicted intracellular proteins, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol

Antibody reliability (HPA): IH enhanced · IF supported

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 (13)

Type	Positions
Phosphoserine	527, 530, 533, 540, 662, 696, 700, 714, 766, 771, 945, 977, 1124

Mutagenesis-validated functional residues (1)

Position	Phenotype
662	restores csnk1e-dependent phosphorylation of variant g-662.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 6; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

6 pathways:

ID	Pathway	Evidence
R-HSA-9909396	Circadian clock	—
R-HSA-9932298	Degradation of CRY and PER proteins	electronic
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	electronic
R-HSA-9931530	Phosphorylation and nuclear translocation of the CRY:PER:kinase complex	electronic
R-HSA-9931512	Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters	electronic
R-HSA-9931521	The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex	electronic

MSigDB gene sets: 365 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, PAX4_01, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT, GOBP_NEUROTRANSMITTER_UPTAKE, GOBP_PHOTOPERIODISM, JAEGER_METASTASIS_DN, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GOBP_INSULIN_SECRETION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_WHITE_FAT_CELL_DIFFERENTIATION, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_REGULATION_OF_HORMONE_LEVELS

GO Biological Process (26): negative regulation of transcription by RNA polymerase II (GO:0000122), response to ischemia (GO:0002931), neural retina development (GO:0003407), glycogen biosynthetic process (GO:0005978), gluconeogenesis (GO:0006094), chromatin remodeling (GO:0006338), DNA-templated transcription (GO:0006351), fatty acid metabolic process (GO:0006631), circadian rhythm (GO:0007623), regulation of vasoconstriction (GO:0019229), lactate biosynthetic process (GO:0019249), negative regulation of protein ubiquitination (GO:0031397), circadian regulation of gene expression (GO:0032922), regulation of circadian rhythm (GO:0042752), negative regulation of circadian rhythm (GO:0042754), entrainment of circadian clock by photoperiod (GO:0043153), negative regulation of DNA-templated transcription (GO:0045892), regulation of neurogenesis (GO:0050767), regulation of insulin secretion (GO:0050796), white fat cell differentiation (GO:0050872), regulation of cell cycle (GO:0051726), regulation of glutamate uptake involved in transmission of nerve impulse (GO:0051946), negative regulation of fat cell proliferation (GO:0070345), positive regulation of cold-induced thermogenesis (GO:0120162), positive regulation of DNA-templated transcription (GO:0045893), rhythmic process (GO:0048511)

GO Molecular Function (4): transcription cis-regulatory region binding (GO:0000976), transcription corepressor binding (GO:0001222), transcription coactivator activity (GO:0003713), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), perinuclear region of cytoplasm (GO:0048471)

Reactome top-level categories

1 top-level categories:

Category	Pathways
Circadian clock	5

GO top-level categories

53 GO namespaces:

Category	Terms
cellular anatomical structure	4
circadian rhythm	3
nuclear lumen	2
cytoplasm	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
response to stress	1
retina development in camera-type eye	1
animal gross anatomical part developmental process	1
glycogen metabolic process	1
glucan biosynthetic process	1
glucose metabolic process	1
hexose biosynthetic process	1
chromatin organization	1
gene expression	1
RNA biosynthetic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
rhythmic process	1
vasoconstriction	1
blood vessel diameter maintenance	1
regulation of blood circulation	1
lactate metabolic process	1
monocarboxylic acid biosynthetic process	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
regulation of gene expression	1
regulation of biological process	1
regulation of circadian rhythm	1
negative regulation of biological process	1
photoperiodism	1
entrainment of circadian clock	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
neurogenesis	1
regulation of nervous system development	1
regulation of cell development	1
insulin secretion	1
regulation of protein secretion	1
regulation of peptide hormone secretion	1
fat cell differentiation	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
transcription coregulator binding	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
binding	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
intracellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 2 of 36 annotations. The rest are phylogenetic / computational / electronic (IEA).

2 experimentally-supported GO terms:

GO term	NS	Evidence
nucleoplasm	CC	direct assay
nucleus	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 1,667 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PER2	CRY1	Q16526	982
PER2	CRY2	Q49AN0	972
PER2	NR1D1	P20393	970
PER2	NR1D2	Q14995	942
PER2	NFIL3	Q16649	928
PER2	BHLHE41	Q9C0J9	925
PER2	RORA	P35397	913
PER2	RORB	Q92753	913
PER2	BHLHE40	O14503	907
PER2	CSNK1E	P49674	880
PER2	TIMELESS	Q9UNS1	859
PER2	CLOCK	O15516	839
PER2	BMAL1	O00327	831
PER2	CSNK1D	P48730	823
PER2	RORC	P51449	822

IntAct

Human interaction partners of PER2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

14 partners by confidence:

Partner	Interaction type	MIscore	Records
CSNK1E	phosphorylation reaction	0.850	7
CSNK1D	phosphorylation reaction	0.810	6
PER1	physical association	0.560	5
ELOA	physical association	0.560	3
LENG8	physical association	0.560	3
LMO4	physical association	0.560	3
MLH1	physical association	0.560	3
UBL4A	physical association	0.560	3
PML	colocalization	0.460	7
CASK	direct interaction	0.440	1
CRY2	association	0.350	2
CIBAR1	association	0.350	1
CRY1	association	0.350	1
TNFRSF14	physical association	0.000	1

BioGRID (193 interactions; top human partners by supporting records): CRY1 (Two-hybrid; 13 records), CRY2 (Two-hybrid; 7 records), BTRC (Affinity Capture-MS; 6 records), MDM2 (Two-hybrid; 6 records), TP53 (Affinity Capture-Western; 6 records), CSNK1E (Two-hybrid; 5 records), CSNK1D (Two-hybrid; 3 records), FBXW11 (Affinity Capture-MS; 2 records), HK1 (Affinity Capture-Western; 2 records), IMPDH2 (Affinity Capture-Western; 2 records), MCM3 (Affinity Capture-Western; 2 records), PER1 (Two-hybrid; 2 records), ACACA (Proximity Label-MS), ACAD11 (Affinity Capture-MS), ACTN1 (Proximity Label-MS)

SIGNOR signaling

showing 20 of 23 signaling interactions:

A	Effect	B	Mechanism
PER2	“down-regulates quantity by repression”	SNAI2	“transcriptional regulation”
PER2	“down-regulates activity”	POU2F1	binding
PER2	“down-regulates quantity by repression”	TWIST1	“transcriptional regulation”
CEBPA	“up-regulates quantity by expression”	PER2	“transcriptional regulation”
PER2	up-regulates	Apoptosis
PER2	down-regulates	Proliferation
BMAL1/NPAS2	“up-regulates quantity by expression”	PER2	“transcriptional regulation”
PER2	“down-regulates activity”	BMAL1/NPAS2	binding
PER2	“down-regulates activity”	CLOCK/BMAL1	binding
CSNK1D	“down-regulates quantity by destabilization”	PER2	phosphorylation
NR3C1	“up-regulates quantity by expression”	PER2	“transcriptional regulation”
SCF-betaTRCP	“down-regulates quantity by destabilization”	PER2	ubiquitination
MDM2	“down-regulates quantity by destabilization”	PER2	polyubiquitination
SIK3	“down-regulates quantity by destabilization”	PER2	phosphorylation
BHLHE40	“down-regulates quantity by repression”	PER2	“transcriptional regulation”
RAI1	“up-regulates quantity by expression”	PER2	“transcriptional regulation”
CSNK1E	“down-regulates quantity by destabilization”	PER2	phosphorylation
ARNTL	“up-regulates quantity by expression”	PER2	“transcriptional regulation”
CLOCK	“up-regulates quantity by expression”	PER2	“transcriptional regulation”
CLOCK/BMAL1	“up-regulates quantity by expression”	PER2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 14 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex	5	324.4×	5e-11

GO biological processes:

GO term	Partners	Fold	FDR
regulation of circadian rhythm	6	119.7×	8e-10
circadian regulation of gene expression	6	108.0×	8e-10

Disease & clinical

Genetic variants

Variant evidence for PER2: 252 ClinVar records (2 pathogenic / likely pathogenic); 8 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	159
Likely benign	57
Benign	15

Top pathogenic / likely-pathogenic (2)

Showing all 2 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
634825	NM_022817.3(PER2):c.595del (p.Leu199fs)	Pathogenic	criteria provided, single submitter	1
6345	NM_022817.3(PER2):c.1984A>G (p.Ser662Gly)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore PER2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 26 predictions of 2,021):

Position(s)	Effect	Δscore	Sites
2:238246525–238246526	acceptor_gain	1.0000	2
2:238246525	acceptor_loss	1.0000
2:238255655–238255656	donor_loss	1.0000	5
2:238256925	donor_gain	1.0000
2:238257091	acceptor_gain	1.0000
2:238258495–238258496	donor_loss	1.0000	4
2:238258645–238258646	acceptor_loss	1.0000	5
2:238259967–238259968	donor_loss	1.0000	5
2:238260055	acceptor_gain	1.0000
2:238260833	donor_gain	1.0000

AlphaMissense

1,247 missense substitutions predicted likely pathogenic (of 8,285 scored), across 340 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F333	8	0.964	0.997
H337	8	0.955	0.987
H432	8	0.954	0.993
D374	8	0.950	0.980
D235	8	0.939	0.970
F343	8	0.930	0.993
F444	8	0.925	0.977
F239	8	0.913	0.987
F427	8	0.906	0.990
D1165	8	0.906	0.963
H382	8	0.902	0.985
F193	8	0.887	0.978
D347	8	0.878	0.963
H733	8	0.863	0.971
F227	8	0.855	0.977
H678	8	0.811	0.944
D588	8	0.795	0.919
D360	8	0.752	0.875
W414	7	0.980	0.999
F417	7	0.971	0.995

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.29e-05
Lung Squamous Cell Carcinoma (validation)	favorable	2.12e-05

Disease associations

OMIM: gene MIM:603426 | disease phenotypes: MIM:604348

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
advanced sleep phase syndrome	Supportive	Autosomal dominant
advanced sleep phase syndrome 1	Limited	Unknown	2

Mondo (2): advanced sleep phase syndrome 1 (MONDO:0011442), advanced sleep phase syndrome (MONDO:0015609)

Orphanet (1): Familial advanced sleep-phase syndrome (Orphanet:164736)

HPO phenotypes

4 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000716	Depression
HP:0006979	Sleep-wake cycle disturbance
HP:0031873	Early chronotype

GWAS associations

8 associations:

Study	Trait	p-value
GCST007576_355	Chronotype	4e-27
GCST003837_8	Chronotype	1e-14
GCST003838_12	Morning vs. evening chronotype	4e-10
GCST003429_55	Morning vs. evening chronotype	3e-9
GCST007576_356	Chronotype	1e-8
GCST003453_1	Chronotype	8e-8
GCST003453_14	Chronotype	8e-8
GCST003454_10	Morning vs. evening chronotype	9e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3751648 (SINGLE PROTEIN), CHEMBL4296116 (PROTEIN COMPLEX)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

388 measured of 389 human assays (389 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-1-carbazol-9-yl-3-(1,1-dioxothiazinan-2-yl)propan-2-ol	EC50	11 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(3,6-difluorocarbazol-9-yl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)propan-2-ol	EC50	20 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
(2S)-1-carbazol-9-yl-3-(1,1-dioxo-1,2-thiazolidin-2-yl)propan-2-ol	EC50	21 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-carbazol-9-yl-3-(5-fluoro-1,1-dioxo-1,2-thiazolidin-2-yl)propan-2-ol	EC50	23 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(3,6-difluorocarbazol-9-yl)-3-(1,1-dioxo-1,2,6-thiadiazinan-2-yl)propan-2-ol	EC50	25 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(1-methylcyclopentyl)methanesulfonamide	EC50	28 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-carbazol-9-yl-3-(1,1-dioxo-3H-1,2-benzothiazol-2-yl)propan-2-ol	EC50	31 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(2,5-difluorocarbazol-9-yl)-3-(1,1-dioxothiazinan-2-yl)propan-2-ol	EC50	32 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-carbazol-9-yl-3-(1,1-dioxo-1,2,6-thiadiazinan-2-yl)propan-2-ol	EC50	33 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-carbazol-9-yl-3-(2,2-dioxo-3,4-dihydro-2lambda6,1-benzothiazin-1-yl)propan-2-ol	EC50	34 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(3,6-difluorocarbazol-9-yl)-3-(1,1-dioxo-1,2,5-thiadiazinan-2-yl)propan-2-ol	EC50	35 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
N-cyclobutyl-N-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]methanesulfonamide	EC50	37 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(2,7-difluorocarbazol-9-yl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)propan-2-ol	EC50	40 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(1-methylcyclobutyl)methanesulfonamide	EC50	41 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-carbazol-9-yl-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-3-methylbutan-2-ol	EC50	42 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
CHEMBL3753487	EC50	42 nM
1-carbazol-9-yl-3-(4-methoxy-1,1-dioxothiazinan-2-yl)propan-2-ol	EC50	44 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(3,6-difluorocarbazol-9-yl)-3-(5,5-difluoro-1,1-dioxo-1,2-thiazolidin-2-yl)propan-2-ol	EC50	45 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(3,6-difluorocarbazol-9-yl)-3-(1,1-dioxothiazinan-2-yl)propan-2-ol	EC50	46 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(2,6-difluorocarbazol-9-yl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)propan-2-ol	EC50	50 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-carbazol-9-yl-3-(6-fluoro-1,1-dioxothiazinan-2-yl)propan-2-ol	EC50	51 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(3-(3,6-difluoro- 9H-carbazol-9-yl)-2- hydroxypropyl)-4- ethylpyrrolidin-2- one	EC50	52 nM	US-10214507
1-(3,6-difluorocarbazol-9-yl)-3-(5-fluoro-1,1-dioxo-1,2-thiazolidin-2-yl)propan-2-ol	EC50	53 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
(1R,4S)-2-((R)-3- (3,6-difluoro-9H- carbazol-9-yl)-2- hydroxypropyl)- 2-azabi- cyclo[2.2.1]heptan- 3-one	EC50	54 nM	US-10214507
1-(3,6-difluorocarbazol-9-yl)-3-(1,1-dioxo-1,2-thiazolidin-2-yl)-3-methylbutan-2-ol	EC50	57 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(3,6-difluorocarbazol-9-yl)-3-(1,1-dioxo-5-propan-2-yl-1,2,5-thiadiazinan-2-yl)propan-2-ol	EC50	59 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(3-(9H-carbazol- 9-yl)-2- hydroxypropyl)-3- fluoropiperidin-2- one	EC50	61 nM	US-10214507
1-(3,6-difluorocarbazol-9-yl)-3-(5,5-dimethyl-1,1-dioxo-1,2-thiazolidin-2-yl)propan-2-ol	EC50	73 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
CHEMBL3754594	EC50	73 nM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(1-methylcyclopropyl)methanesulfonamide	EC50	76 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(3,6-difluorocarbazol-9-yl)-3-(4-methyl-1,1-dioxo-1,2-thiazolidin-2-yl)propan-2-ol	EC50	78 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(3-(3,6-difluoro- 9H-carbazol-9-yl)-2- hydroxypropyl)-3- fluoropiperidin-2- one	EC50	79 nM
1-(3-(3,6-difluoro- 9H-carbazol-9-yl)-2- hydroxypropyl)-3- isopropylpiperidin- 2-one	EC50	79 nM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(3-methylcyclobutyl)methanesulfonamide	EC50	79 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(3,6-difluorocarbazol-9-yl)-2-methyl-3-(5-methyl-1,1-dioxo-1,2,5-thiadiazinan-2-yl)propan-2-ol	EC50	80 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
N-cyclopropyl-N-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]methanesulfonamide	EC50	81 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
N-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-N-(1-methylcyclobutyl)methanesulfonamide	EC50	83 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-carbazol-9-yl-3-(6-methyl-1,1-dioxothiazinan-2-yl)propan-2-ol	EC50	84 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(3,6-difluorocarbazol-9-yl)-3-(5-methyl-1,1-dioxo-1,2,5-thiadiazinan-2-yl)propan-2-ol	EC50	86 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
(1R,4S)-2-((R)-3- (9H-carbazol-9-yl)- 2-hydroxypropyl)- 2-azabi- cyclo[2.2.1]heptan- 3-one	EC50	89 nM	US-10214507
(R)-1-((R)-3-(9H- carbazol-9-yl)-2- hydroxypropyl)-5- methylpyrrolidin-2- one	EC50	95 nM	US-10214507
N-[3-(2,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-N-propan-2-ylmethanesulfonamide	EC50	95 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-methylmethanesulfonamide	EC50	100 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-propan-2-ylmethanesulfonamide	EC50	100 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(2-methylpropyl)methanesulfonamide	EC50	100 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(2-methylcyclopentyl)methanesulfonamide	EC50	113 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
(1S,4R)-2-[(2R)-3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-2-azabicyclo[2.2.1]heptan-3-one	EC50	115 nM	US-10214507
(R)-1-((R)-3-(9H- carbazol-9-yl)-2- hydroxypropyl)-3- methylpyrrolidin-2- one	EC50	120 nM	US-10214507
N-(3-carbazol-9-yl-2-hydroxypropyl)methanesulfonamide	EC50	123 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators
1-(3,6-difluorocarbazol-9-yl)-3-(1,1-dioxo-1,2,5-thiadiazinan-2-yl)-2-methylpropan-2-ol	EC50	125 nM	US-10383880: Carbazole-containing sulfonamides as cryptochrome modulators

ChEMBL bioactivities

617 potent at pChembl≥5 of 618 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.96	EC50	11	nM	CHEMBL4277833
7.70	EC50	20	nM	CHEMBL4288250
7.68	EC50	21	nM	CHEMBL4286916
7.64	EC50	23	nM	CHEMBL4286923
7.60	EC50	25	nM	CHEMBL4290598
7.55	EC50	28	nM	CHEMBL4279225
7.54	EC50	29	nM	CHEMBL3753839
7.51	EC50	31	nM	CHEMBL4289135
7.50	EC50	32	nM	CHEMBL4283290
7.48	EC50	33	nM	CHEMBL3753932
7.47	EC50	34	nM	CHEMBL4292685
7.46	EC50	35	nM	CHEMBL3752502
7.46	EC50	35	nM	CHEMBL3752819
7.46	EC50	35	nM	CHEMBL5912357
7.43	EC50	37	nM	CHEMBL4287967
7.40	EC50	40	nM	CHEMBL4288718
7.39	EC50	41	nM	CHEMBL4294270
7.38	EC50	42	nM	CHEMBL3753487
7.38	EC50	42	nM	CHEMBL4289790
7.36	EC50	44	nM	CHEMBL4286068
7.35	EC50	45	nM	CHEMBL4283783
7.34	EC50	46	nM	CHEMBL4281214
7.30	EC50	50	nM	CHEMBL4290327
7.29	EC50	51	nM	CHEMBL4292041
7.28	EC50	52	nM	CHEMBL5937043
7.28	EC50	53	nM	CHEMBL4290336
7.27	EC50	54	nM	CHEMBL5987511
7.24	EC50	57	nM	CHEMBL4283668
7.23	EC50	59	nM	CHEMBL5787495
7.21	EC50	61	nM	CHEMBL5960297
7.14	EC50	73	nM	CHEMBL3754594
7.14	EC50	73	nM	CHEMBL4284123
7.12	EC50	76	nM	CHEMBL4287301
7.11	EC50	78	nM	CHEMBL4292482
7.10	EC50	79	nM	CHEMBL4215584
7.10	EC50	79	nM	CHEMBL4204045
7.10	EC50	79	nM	CHEMBL4280285
7.10	EC50	80	nM	CHEMBL6005354
7.09	EC50	81	nM	CHEMBL4277405
7.08	EC50	84	nM	CHEMBL4285073
7.08	EC50	83	nM	CHEMBL4281175
7.07	EC50	86	nM	CHEMBL5793672
7.05	EC50	89	nM	CHEMBL5748944
7.05	EC50	90	nM	CHEMBL1446115
7.02	EC50	95	nM	CHEMBL5887333
7.02	EC50	95	nM	CHEMBL4284237
7.00	EC50	100	nM	CHEMBL1487843
7.00	EC50	100	nM	CHEMBL3753078
7.00	EC50	100	nM	CHEMBL3752323
6.95	EC50	113	nM	CHEMBL4284751

PubChem BioAssay actives

94 with measured affinity, of 135 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-carbazol-9-yl-3-(1,1-dioxo-1,2,5-thiadiazolidin-2-yl)propan-2-ol	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.0420	uM
1-carbazol-9-yl-3-(3,3-dioxo-1,3,4-oxathiazinan-4-yl)propan-2-ol	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.0730	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-propan-2-ylpiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.0790	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-fluoropiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.0790	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-4-methylpiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1280	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-cyclobutylmethanesulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.1290	uM
1-carbazol-9-yl-3-(5-methyl-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)propan-2-ol	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.1320	uM
1-carbazol-9-yl-3-(1,1-dioxo-1,2-thiazolidin-2-yl)propan-2-ol	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.1440	uM
3-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-azabicyclo[4.1.0]heptan-4-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1490	uM
2-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-2-azabicyclo[2.2.1]heptan-3-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1630	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3,3-dimethylpyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1640	uM
3-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-azabicyclo[4.1.0]heptan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1670	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-phenyl-1,3-diazinan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1710	uM
1-carbazol-9-yl-3-(1,1-dioxothiazinan-2-yl)propan-2-ol	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.1730	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(2-methylpropyl)methanesulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.1780	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-1,3-diazinan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1880	uM
1-carbazol-9-yl-3-(1,1-dioxothiazetidin-2-yl)propan-2-ol	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.1900	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]piperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1920	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3,3-difluoropiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1940	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(furan-2-ylmethyl)ethanesulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.1970	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-5-methylpyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.1990	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-fluoropyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.2080	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-5-methylpiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.2240	uM
3-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-azabicyclo[3.1.0]hexan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.2460	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-propan-2-ylpyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.2610	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-phenylmethanesulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.2720	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(furan-2-ylmethyl)-2-methoxyethanesulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.2880	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-cyclopentylmethanesulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.3080	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-methoxypiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.3300	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-ethylpiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.3320	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(furan-2-ylmethyl)-2-methylpropane-1-sulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.3610	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]imidazolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.3630	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(furan-2-ylmethyl)butane-1-sulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.3740	uM
1-carbazol-9-yl-3-(1,1-dioxo-1,2,6-thiadiazinan-2-yl)propan-2-ol	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.3840	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-5-methoxypiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.3970	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(3-fluorophenyl)methanesulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.4000	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-methylimidazolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4060	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-propylmethanesulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.4080	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(furan-2-ylmethyl)-1-phenylmethanesulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.4150	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-ethylpyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4170	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-4-methyl-1,3-diazinan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4170	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-methylpyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4240	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-(furan-2-ylmethyl)propane-2-sulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.4380	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-cyclopropylmethanesulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.4460	uM
4-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]morpholin-3-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4470	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3,3-dimethylpiperidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4630	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)methanesulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.4790	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-phenylpyrrolidin-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4870	uM
1-[3-(3,6-difluorocarbazol-9-yl)-2-hydroxypropyl]-3-ethyl-1,3-diazinan-2-one	1370816: Modulation activity at CRY2/PER2 in human U2OS cells harboring per2-dLuc assessed as activation of per2 activity measured every 100 mins for 5 days by luciferase reporter gene assay	ec50	0.4970	uM
N-(3-carbazol-9-yl-2-hydroxypropyl)-N-ethylmethanesulfonamide	1272827: Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	ec50	0.5050	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	7
Arsenic Trioxide	decreases expression	3
Hydrogen Peroxide	affects expression, affects reaction, affects cotreatment	3
bisphenol A	increases methylation, affects cotreatment, increases expression	2
epigallocatechin gallate	affects cotreatment, affects expression, affects reaction, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Arsenic	decreases expression, increases abundance, affects expression	2
Dexamethasone	affects expression, affects cotreatment, increases expression	2
Phenobarbital	affects expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Particulate Matter	increases methylation, decreases expression	2
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
lead acetate	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
trichostatin A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
zinc chromate	increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression, affects cotreatment	1
butylbenzyl phthalate	increases expression	1
aflatoxin B2	increases methylation	1
pentanal	decreases expression	1
gallocatechol	affects reaction, affects cotreatment, affects expression	1
2-(4-(2-carboxyethyl)phenethylamino)-5’-N-ethylcarboxamidoadenosine	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3757653	Binding	Reduction of amplitude effect of PER2 in human U2OS cells harboring Per2-dLuc luciferase reporter gene assessed as effects on circadian rhythms	Carbazole-containing sulfonamides and sulfamides: Discovery of cryptochrome modulators as antidiabetic agents. — *Bioorg Med Chem Lett*

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C0QF	U2OS-PER2-BioID2	Cancer cell line	Female
CVCL_D1Y8	Abcam A-549 PER2 KO	Cancer cell line	Male
CVCL_D2CF	Abcam HCT 116 PER2 KO	Cancer cell line	Male
CVCL_F1NY	HyCyte H4 KO-hPER2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 303 trials:

NCT	Phase	Status	Title
NCT00391261	Phase 4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	Phase 4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	Phase 4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	Phase 4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	Phase 4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	Phase 4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	Phase 4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	Phase 4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	Phase 4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	Phase 4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	Phase 4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	Phase 4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	Phase 4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	Phase 4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	Phase 4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	Phase 4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	Phase 4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	Phase 4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	Phase 4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	Phase 4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	Phase 4	RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT07770152	Phase 4	NOT_YET_RECRUITING	Semaglutide in Youth With Autism Spectrum Disorder
NCT01302964	Phase 3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	Phase 3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	Phase 3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	Phase 3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	Phase 3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	Phase 3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	Phase 3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	Phase 3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	Phase 3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	Phase 3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	Phase 3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	Phase 3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	Phase 3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	Phase 3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	Phase 3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	Phase 3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	Phase 3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	Phase 3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	Phase 3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder
NCT06333964	Phase 3	COMPLETED	A Study to Evaluate the Efficacy and Safety of AST-001 in ASD Children
NCT07257939	Phase 3	NOT_YET_RECRUITING	NTI164 in Autism Spectrum Disorder
NCT07655115	Phase 3	RECRUITING	Single Dose Double-blind, Placebo-controlled Cross-over (SDDBPCCO) Shiftability Study, Will be Followed by a 10-week Open-label Study With Arbaclofen (4 Weeks of Titration and Then 6 Weeks of Active/Stable Treatment). The Effects of Arbaclofen on Target EEG and ERG Metrics Will be Associated With th
NCT00251303	Phase 2	COMPLETED	Riluzole to Treat Child and Adolescent Obsessive-Compulsive Disorder With or Without Autism Spectrum Disorders
NCT00614198	Phase 2	COMPLETED	ScanBrit Dietary Intervention in Autism
NCT00619190	Phase 2	COMPLETED	Study of Aripiprazole to Treat Children and Adolescents With Autism
NCT00709202	Phase 2	COMPLETED	Efficacy and Tolerability Study of Betahistine to Ameliorate Antipsychotic Associated Weight Gain
NCT00846547	Phase 2	COMPLETED	Open-Label Study of the Safety and Tolerability of STX209 in Subjects With Autism Spectrum Disorders
NCT01064973	Phase 2	TERMINATED	An Open Label Extension Study of STX209 in Subjects With Autism Spectrum Disorders
NCT01170325	Phase 2	WITHDRAWN	A Study of Divalproex Sodium in Children With ASD and Epileptiform EEG
NCT01205282	Phase 2	COMPLETED	Dose Finding Study of Pioglitazone in Children With Autism Spectrum Disorders (ASD) (PIO)
NCT01248130	Phase 2	TERMINATED	Omega-3 Fatty Acids Monotherapy in Children and Adolescents With Autism Spectrum Disorders
NCT01248728	Phase 2	COMPLETED	Omega-3 Fatty Acids For Treatment Of Young Children With Autism (OMG)
NCT01256060	Phase 2	COMPLETED	Intranasal Oxytocin for the Treatment of Children and Adolescents With ASD (OXY)
NCT01288716	Phase 2	COMPLETED	Study of Arbaclofen for the Treatment of Social Withdrawal in Subjects With Autism Spectrum Disorders
NCT01300923	Phase 2	COMPLETED	Acamprosate in Youth With Fragile X Syndrome
NCT01366859	Phase 2	COMPLETED	Nutritional Intervention in Children With Autism Using Whey Protein (Immunocal): Impact on Core Areas of Behavior
NCT01372449	Phase 2	COMPLETED	A Multi-site Double-blind Placebo-controlled Trial of Memantine Versus Placebo in Children With Autism (MEM)
NCT01395953	Phase 2	WITHDRAWN	Double-blind Trial of Buspirone for the Treatment of Anxiety in Youth With Autism Spectrum Disorders

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PER2 across ~30M SureChEMBL compounds — explore on Sugi Predict.