Is CLOCK p.Met536Thr (c.1607T>C) pathogenic?

CLOCK p.Met536Thr (c.1607T>C) is classified Uncertain significance in CLOCK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: ambiguous (0.5352); Absent from gnomAD v4.1.

How common is CLOCK p.Met536Thr (c.1607T>C) in the general population?

CLOCK p.Met536Thr (c.1607T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLOCK p.Met536Thr (c.1607T>C)?

AlphaMissense predicts ambiguous (score 0.5352) — an in-silico prediction, not a clinical call.

CLOCK p.Met536Thr

c.1607T>C · VCV4230091

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5352 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5352	ambiguous
REVEL	0.166	moderately benign-leaning
SaProt	LLR -5.46	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 18 kb · p 0.11 · regional, not allelic
Overall
CADD	24.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLOCK
Protein: p.Met536Thr
Coding: c.1607T>C
MANE Select: NM_004898
Type: single nucleotide variant
Location: chr4:55444718 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 61.90 · 2 PDB
Residue 536: the 'interaction with nr3c1' region; the 'interaction with sirt1' region; the 'implicated in the circadian rhythmicity' region

Full CLOCK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLOCK p.Met536Val Uncertain significance ★ ⚠ same residue
CLOCK c.674-10A>G Benign ★★ same type
CLOCK p.Ala34= Benign ★★ same type
CLOCK p.Gly235Glu Likely benign ★★ same type
CLOCK c.2362-2A>G Uncertain significance ★ same type
CLOCK p.Ala432Pro Uncertain significance ★ ⚠ same type
CLOCK p.Ala691Gly Uncertain significance ★ ⚠ same type
CLOCK p.Arg242Lys 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/clock-p-met536thr (accessed [today's date]).

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