Is TIMELESS p.Phe278Ser (c.833T>C) pathogenic?

TIMELESS p.Phe278Ser (c.833T>C) is classified Uncertain significance in TIMELESS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-12). AlphaMissense: likely pathogenic (0.9667); Very rare (popmax 0.00691%, afr).

How common is TIMELESS p.Phe278Ser (c.833T>C) in the general population?

TIMELESS p.Phe278Ser (c.833T>C) is very rare (popmax 0.00691%, afr) (gnomAD).

What do computational predictors say about TIMELESS p.Phe278Ser (c.833T>C)?

AlphaMissense predicts likely pathogenic (score 0.9667) — an in-silico prediction, not a clinical call.

TIMELESS p.Phe278Ser

c.833T>C · rs142429793 · VCV2343098

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9667 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00691%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9667	likely pathogenic · top 2% in TIMELESS
REVEL	0.848	moderately pathogenic-leaning
SaProt	LLR -13.76	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 16 kb · p 0.072 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00691% African / African-American · 5/72,378 alleles

Filtering AF 0.00362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00325%

Overall 0.0038% 60/1,580,666 alleles · very rare exomes 55/1,428,472 · genomes 5/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00691%	14,476
European (non-Finnish)	0.00462%	21,622
Ashkenazi Jewishnot grpmax-eligible	0.00352%	28,392

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.Phe278Ser
Coding: c.833T>C
MANE Select: NM_003920
dbSNP: rs142429793
Type: single nucleotide variant
Location: chr12:56430957 (GRCh38)
Gene constraint: LOEUF 0.857 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.56 · 9 PDB
Residue 278: the 'required for homodimerization and for interaction with cry1 and chek1' 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-phe278ser (accessed [today's date]).

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