Is TIMELESS p.Leu607Pro (c.1820T>C) pathogenic?

TIMELESS p.Leu607Pro (c.1820T>C) is classified Uncertain significance in TIMELESS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: likely pathogenic (0.9759); Ultra-rare (popmax 0.0164%, mid).

How common is TIMELESS p.Leu607Pro (c.1820T>C) in the general population?

TIMELESS p.Leu607Pro (c.1820T>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about TIMELESS p.Leu607Pro (c.1820T>C)?

AlphaMissense predicts likely pathogenic (score 0.9759) — an in-silico prediction, not a clinical call.

TIMELESS p.Leu607Pro

c.1820T>C · VCV3456597

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9759 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9759	likely pathogenic · top 1% in TIMELESS
REVEL	0.477	indeterminate
SaProt	LLR -13.82	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 11	GERP 0.73, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 16 kb · p 0.072 · regional, not allelic
Overall
CADD	29.2	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00118% 19/1,614,054 alleles · ultra-rare exomes 16/1,461,888 · genomes 3/152,166 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.01%	9,999
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.000847%	118,004

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.Leu607Pro
Coding: c.1820T>C
MANE Select: NM_003920
Type: single nucleotide variant
Location: chr12:56424810 (GRCh38)
Gene constraint: LOEUF 0.857 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.56 · 9 PDB

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-leu607pro (accessed [today's date]).

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