Is TIMELESS p.Pro1088Ser (c.3262C>T) pathogenic?

TIMELESS p.Pro1088Ser (c.3262C>T) is classified Uncertain significance in TIMELESS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-05). AlphaMissense: likely benign (0.0954); Very rare (popmax 8.48e-05%, nfe).

How common is TIMELESS p.Pro1088Ser (c.3262C>T) in the general population?

TIMELESS p.Pro1088Ser (c.3262C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TIMELESS p.Pro1088Ser (c.3262C>T)?

AlphaMissense predicts likely benign (score 0.0954) — an in-silico prediction, not a clinical call.

TIMELESS p.Pro1088Ser

c.3262C>T · rs267603582 · VCV2270347

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0954	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -7.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.26, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 16 kb · p 0.072 · regional, not allelic
Overall
CADD	17.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,434 alleles

Overall 6.2e-05% 1/1,612,768 alleles · very rare exomes 1/1,460,498 · genomes 0/152,270 · joint denominator

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.Pro1088Ser
Coding: c.3262C>T
MANE Select: NM_003920
dbSNP: rs267603582
Type: single nucleotide variant
Location: chr12:56418326 (GRCh38)
Gene constraint: LOEUF 0.857 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.56 · 9 PDB
Residue 1088: an α-helix; 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 'interaction with parp1' region

Full TIMELESS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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-pro1088ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown