PER2

Chr 2AD

period circadian regulator 2

Also known as: FASPS, FASPS1

NCBI Gene: 8864 ENSG00000132326 UniProt: O15055 OMIM: 603426

The PER2 protein is a transcriptional repressor that forms a core component of the circadian clock, regulating approximately 24-hour rhythms in gene expression that control sleep, metabolism, body temperature, and other physiological processes through feedback loops in both central brain circuits and peripheral tissues. Mutations cause familial advanced sleep phase syndrome type 1, inherited in an autosomal dominant pattern. This gene shows high constraint against loss-of-function variants (LOEUF 0.347), indicating that such variants are likely to be pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Jan 2014]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Advanced sleep phase syndrome, familial, 1MIM #604348

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

314

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.35

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.35LOEUF

pLI 0.715

Z-score 5.31

OE 0.21 (0.13–0.35)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.43Z-score

OE missense 0.96 (0.90–1.02)

706 obs / 738.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.21 (0.13–0.35)

0≤0.351.4

Missense OE?0.96 (0.90–1.02)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 11 / 52.5Missense obs/exp: 706 / 738.6Syn Z: -0.50

Background carrier burden — how many people carry a rare variant somewhere in PER2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 37

1,624 rare PASS variants

Rare truncating (LoF)

1 in 1,200

177 rare PASS variants

Rare synonymous (reference)

1 in 58

728 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PER2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 50	1 in 1,200
South Asian	~43k	1 in 32	1 in 840
Remaining (unassigned)	~30k	1 in 26	1 in 1,200
European (Finnish)	~27k	1 in 120	1 in 650
Admixed American	~22k	1 in 31	1 in 2,200
African / African American	~21k	1 in 27	1 in 1,200
East Asian	~20k	1 in 36	≈ 1 in 4,000
Ashkenazi Jewish	~13k	1 in 140	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 33	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 19 of 22 coding exons well covered in gnomAD exomes; exons 9, 14, 23 marginal. Genomes: all 22.? see exons ↓