| Gene | Variant / protein change | Human evidence | Functional consequence | Model evidence | Confidence / caveat |
|---|---|---|---|---|---|
| **PER2** | **S662G** | Landmark FASPS family study localized disease to chromosome 2qter and identified a serine-to-glycine change in the CKIε-binding region of hPER2; autosomal dominant segregation reported in the original family (pqac-00000006, pqac-00000016) | Causes **hypophosphorylation by CKIε in vitro**; interpreted as altering clock timing/period and producing phase advance (pqac-00000006, pqac-00000016) | Animal-model details not directly verified in gathered evidence; later reviews state rare advanced-SWPD variants were functionally linked to phosphorylation changes in mice, but not variant-specific here (pqac-00000004, pqac-00000013) | **Established** FASPS gene/variant pair; exact HGVS genomic/cDNA notation not verified in gathered evidence |
| **CSNK1D** | **T44A** | Included by reviews as a rare Mendelian advanced-SWPD / FASP gene; familial autosomal dominant evidence is referenced in review literature, but the primary report was not directly retrieved here (pqac-00000002, pqac-00000004, pqac-00000013) | Review-level evidence indicates altered circadian phosphorylation biology and shortened physiological circadian cycle, but variant-specific mechanism was **not directly verified in gathered evidence** (pqac-00000001, pqac-00000004) | Review-level statement notes functional links to phosphorylation changes in mice for rare advanced-SWPD variants broadly; **T44A-specific model details not directly verified here** (pqac-00000004, pqac-00000013) | **Established gene, variant included as likely established candidate**, but this table cannot verify the exact primary-study details beyond review support |
| **CRY2** | **A260T** | Review and PNAS background text identify **CRY2** as a prior FASP gene; exact A260T variant is commonly cited for FASP, but the primary human report was **not directly retrieved** in gathered evidence (pqac-00000004, pqac-00000014) | Background text states prior FASP mutations in negative regulators share **PER/CRY instability** and derepression of BMAL1/CLOCK; applying that specifically to A260T is **inference from review/background, not directly verified here** (pqac-00000014) | No A260T-specific animal/cellular model details directly verified in gathered evidence | **Candidate/likely established variant in field**, but variant-specific human and mechanistic details were not directly verified in the retrieved primary evidence |
| **PER3** | **P415A / H417R** | Review/background sources state **PER3** mutations have been reported in FASP; a 2024 paper on **PER2/PER3 variants** was unobtainable, and exact primary evidence for the double substitution was not directly retrieved (pqac-00000004, pqac-00000014) | PNAS background states prior FASP mutations in PER2/CRY2/PER3 show **instability of PER and CRY**, causing derepression of BMAL1/CLOCK and shortened period, but **PER3 P415A/H417R-specific mechanism was not directly verified** (pqac-00000014) | No PER3 P415A/H417R-specific model evidence directly verified in gathered evidence | **Candidate/field-recognized association**, but the specific variant-level evidence remains indirect in this evidence set |
| **TIMELESS** | **R1081X** | PNAS primary study reports a **small family with two FASP individuals and one non-FASP subject**; mutation in **human TIMELESS** reported as causing FASP (pqac-00000005, pqac-00000007, pqac-00000014) | Prevents TIM nuclear accumulation, causes **exclusive cytoplasmic localization**, **lower stability**, **reduced affinity for CRY2**, weakened CLOCK-BMAL1 repression, and destabilization of the **PER/CRY complex**; alters light entrainment with preserved organismal period (pqac-00000005, pqac-00000007, pqac-00000014) | **CRISPR mutant mice** recapitulated advanced sleep phase with altered photic entrainment and normal circadian period; shortened period seen in CRISPR-generated cells and MEFs (pqac-00000005, pqac-00000007, pqac-00000014) | **Established but rare**; family was small and variant was reported absent from public databases as of the study period; strongest evidence among newer genes in gathered set |


*Table: This table summarizes established and candidate familial advanced sleep phase genes and variants requested by the user, separating directly verified evidence from review-level or indirect support. It is useful for distinguishing high-confidence variant-mechanism pairs from associations that require primary-source confirmation.*