Is TIMELESS p.Ala129Ser (c.385G>T) pathogenic?

TIMELESS p.Ala129Ser (c.385G>T) is classified Benign/Likely benign in TIMELESS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-18). AlphaMissense: likely benign (0.1107); Low-frequency (popmax 2.57%, sas).

How common is TIMELESS p.Ala129Ser (c.385G>T) in the general population?

TIMELESS p.Ala129Ser (c.385G>T) is low-frequency (popmax 2.57%, sas) (gnomAD).

What do computational predictors say about TIMELESS p.Ala129Ser (c.385G>T)?

AlphaMissense predicts likely benign (score 0.1107) — an in-silico prediction, not a clinical call.

TIMELESS p.Ala129Ser

c.385G>T · rs72478986 · VCV730313

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1107 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.57%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1107	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -7.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.13	GERP -3.1, phastCons 0.69
Regional constraint	o/e 0.95	unconstrained · MANE · 16 kb · p 0.072 · regional, not allelic
Overall
CADD	17.88	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 2.57% South Asian · 2,340/91,080 alleles

Filtering AF 2.48% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.45%

Overall 0.676% 10,911/1,614,200 alleles · low-frequency exomes 10,049/1,461,886 · genomes 862/152,314 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	2.57%	39
Amishnot grpmax-eligible	1.87%	54
Middle Eastern	1.52%	66
Finnishnot grpmax-eligible	0.859%	116
Remaining individualsnot grpmax-eligible	0.658%	152
European (non-Finnish)	0.597%	168
Ashkenazi Jewishnot grpmax-eligible	0.547%	183
Admixed American	0.383%	261
African / African-American	0.0866%	1,155
East Asian	0.00668%	14,962

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.Ala129Ser
Coding: c.385G>T
MANE Select: NM_003920
dbSNP: rs72478986
Type: single nucleotide variant
Location: chr12:56433425 (GRCh38)
Gene constraint: LOEUF 0.857 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.56 · 9 PDB
Residue 129: the 'required for homodimerization and for interaction with cry1 and chek1' region; a UniProt-annotated variant site (in); 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.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
TIMELESS p.Ala1041Gly 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-ala129ser (accessed [today's date]).

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