TIMELESS p.Pro1160=
c.3480G>A · VCV3256974
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
rare (popmax 0.347%, amr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -2.8 | GERP -2.9 |
| Overall | ||
| CADD | 5.482 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.347%
Admixed American · 208/60,008 alleles
Filtering AF
0.308%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.293%
Overall
0.0995%
1,606/1,614,180 alleles · rare
exomes 1,461/1,461,892 · genomes 145/152,288 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.347% | 289 |
| Remaining individualsnot grpmax-eligible | 0.115% | 868 |
| European (non-Finnish) | 0.106% | 945 |
| Ashkenazi Jewishnot grpmax-eligible | 0.0608% | 1,645 |
| Finnishnot grpmax-eligible | 0.0547% | 1,829 |
| African / African-American | 0.0293% | 3,411 |
| East Asian | 0.00223% | 44,888 |
| South Asian | 0.0011% | 91,090 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- TIMELESS
- Protein
- p.Pro1160=
- Coding
- c.3480G>A
- MANE Select
- NM_003920
- Type
- single nucleotide variant
- Location
- chr12:56417983 (GRCh38)
- Gene constraint
- LOEUF 0.857 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 74.56 · 9 PDB
- Residue 1160
- a UniProt-annotated variant site (in fasps4; reduced protein stability; mislocalization in cytoplasm; reduced interaction with cry2; enhanced destabilization of the per2-cry2 complex; reduced repressor activity of clock|npas2-artnl/bmal1|artnl2/bmal2-induced transactivation of per1; does not affect interaction with per2); the 'disordered' region
Similar variants
- TIMELESS p.Pro1160Leu Uncertain significance ★ ⚠ same residue
- TIMELESS p.Asn337Ser Uncertain significance ★★ ⚠ same type
- TIMELESS p.Ala1145= Benign/Likely benign ★★ same type
- TIMELESS p.Ala129Ser Benign/Likely benign ★★ same type
- TIMELESS p.Arg905Trp Benign/Likely benign ★★ ⚠ same type
- TIMELESS p.Met578Val Benign ★★ same type
- TIMELESS p.Phe1060Leu Benign ★★ same type
- TIMELESS p.Phe509= Benign ★★ same type
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/timeless-p-pro1160 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown