Is TIMELESS p.Arg333Cys (c.997C>T) pathogenic?

TIMELESS p.Arg333Cys (c.997C>T) is classified Uncertain significance in TIMELESS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-28). AlphaMissense: likely benign (0.1356); Very rare (popmax 0.0011%, sas).

How common is TIMELESS p.Arg333Cys (c.997C>T) in the general population?

TIMELESS p.Arg333Cys (c.997C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TIMELESS p.Arg333Cys (c.997C>T)?

AlphaMissense predicts likely benign (score 0.1356) — an in-silico prediction, not a clinical call.

TIMELESS p.Arg333Cys

c.997C>T · rs746965893 · VCV2490172

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1356 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1356	likely benign
REVEL	0.569	indeterminate
SaProt	LLR -10.32	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 16 kb · p 0.072 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,613,996 alleles · very rare exomes 5/1,461,864 · genomes 1/152,132 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,086
European (non-Finnish)	0.000424%	236,007

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.Arg333Cys
Coding: c.997C>T
MANE Select: NM_003920
dbSNP: rs746965893
Type: single nucleotide variant
Location: chr12:56430194 (GRCh38)
Gene constraint: LOEUF 0.857 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.56 · 9 PDB
Residue 333: 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-arg333cys (accessed [today's date]).

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