PER3

Chr 1AD

period circadian regulator 3

Also known as: FASPS3, GIG13

NCBI Gene: 8863 ENSG00000049246 UniProt: P56645 OMIM: 603427

The PER3 protein is a component of the circadian clock system that functions in a transcriptional feedback loop to regulate circadian rhythms and plays an important role in sleep-wake timing and sleep homeostasis. Polymorphisms in this gene have been linked to sleep disorders, though the gene is not highly constrained against loss-of-function variants. The inheritance pattern for PER3-related sleep disorders has not been clearly established from the available data.

OMIM ResearchSummary from RefSeq, 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 have been linked to sleep disorders. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.841 OMIM phenotype

Clinical Summary— PER3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 169 VUS of 263 total submissions

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Clinical Trials

6 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.84LOEUF

pLI 0.000

Z-score 2.53

OE 0.64 (0.49–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.11Z-score

OE missense 1.01 (0.95–1.08)

701 obs / 693.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.64 (0.49–0.84)

0≤0.351.4

Missense OE?1.01 (0.95–1.08)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 36 / 56.5Missense obs/exp: 701 / 693.0Syn Z: -1.26

This gene — mechanism propensity

0.6454th %ile

GOF

0.5857th %ile

LOF

0.49top 25%

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

LOF60% of P/LP variants are LoF

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

263 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic3

VUS169

Likely Benign43

Benign13

Conflicting4

Pathogenic

Likely Pathogenic

169

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	1	0	2
Likely Pathogenic	3	0	0	0	3
VUS	4	165	0	0	169
Likely Benign	1	28	4	10	43
Benign	2	4	1	6	13
Conflicting	—				4
Total	10	198	6	16	234

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

48 pathogenic / likely-pathogenic (of 58) ClinVar copy-number / structural variants overlap PER3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →