Is TIMELESS p.Arg435Trp (c.1303C>T) pathogenic?

TIMELESS p.Arg435Trp (c.1303C>T) is classified Uncertain significance in TIMELESS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-27). AlphaMissense: likely pathogenic (0.7511); Ultra-rare (popmax 0.0256%, nfe).

How common is TIMELESS p.Arg435Trp (c.1303C>T) in the general population?

TIMELESS p.Arg435Trp (c.1303C>T) is ultra-rare (popmax 0.0256%, nfe) (gnomAD).

What do computational predictors say about TIMELESS p.Arg435Trp (c.1303C>T)?

AlphaMissense predicts likely pathogenic (score 0.7511) — an in-silico prediction, not a clinical call.

TIMELESS p.Arg435Trp

c.1303C>T · rs200957081 · VCV2368842

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7511 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0256%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7511	likely pathogenic
REVEL	0.472	indeterminate
SaProt	LLR -12.61	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 0.38, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 16 kb · p 0.072 · regional, not allelic
Overall
CADD	26.9	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 0.0256% European (non-Finnish) · 302/1,179,926 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0223%

Overall 0.0201% 325/1,613,222 alleles · ultra-rare exomes 304/1,461,092 · genomes 21/152,130 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0256%	3,907
African / African-American	0.016%	6,240
Remaining individualsnot grpmax-eligible	0.0128%	7,802
Admixed American	0.00167%	59,990
Finnishnot grpmax-eligible	0.00156%	64,012
South Asian	0.0011%	91,022

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.Arg435Trp
Coding: c.1303C>T
MANE Select: NM_003920
dbSNP: rs200957081
Type: single nucleotide variant
Location: chr12:56428884 (GRCh38)
Gene constraint: LOEUF 0.857 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.56 · 9 PDB
Residue 435: an α-helix

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-arg435trp (accessed [today's date]).

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