TIMELESS p.Leu835=
c.2505C>T · rs764646065 · VCV2643094
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0967%, 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 -4.8 | GERP -2.8 |
| Overall | ||
| CADD | 2.695 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0967%
Admixed American · 58/59,988 alleles
Filtering AF
0.0768%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0696%
Overall
0.00446%
72/1,613,992 alleles · ultra-rare
exomes 67/1,461,878 · genomes 5/152,114 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0967% | 1,034 |
| Remaining individualsnot grpmax-eligible | 0.0048% | 20,827 |
| African / African-American | 0.00401% | 24,967 |
| East Asian | 0.00223% | 44,890 |
| South Asian | 0.0011% | 91,082 |
| European (non-Finnish) | 0.000508% | 196,671 |
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.Leu835=
- Coding
- c.2505C>T
- MANE Select
- NM_003920
- dbSNP
- rs764646065
- Type
- single nucleotide variant
- Location
- chr12:56422125 (GRCh38)
- Gene constraint
- LOEUF 0.857 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 74.56 · 9 PDB
- Residue 835
- the 'dna-binding domain' region; an α-helix
Similar variants
- 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
- TIMELESS c.909+5G>A Uncertain significance ★ 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-leu835 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown