Is CLOCK p.Met611Val (c.1831A>G) pathogenic?

CLOCK p.Met611Val (c.1831A>G) is classified Uncertain significance in CLOCK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: likely benign (0.0668); Ultra-rare (popmax 0.0654%, afr).

How common is CLOCK p.Met611Val (c.1831A>G) in the general population?

CLOCK p.Met611Val (c.1831A>G) is ultra-rare (popmax 0.0654%, afr) (gnomAD).

What do computational predictors say about CLOCK p.Met611Val (c.1831A>G)?

AlphaMissense predicts likely benign (score 0.0668) — an in-silico prediction, not a clinical call.

CLOCK p.Met611Val

c.1831A>G · VCV3267828

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0668 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0654%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0668	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -5.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.86	GERP -2.5, phastCons 0.99
Regional constraint	o/e 0.93	unconstrained · MANE · 18 kb · p 0.11 · regional, not allelic
Overall
CADD	11.55	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0654% African / African-American · 49/74,936 alleles

Filtering AF 0.0507% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0456%

Overall 0.00347% 56/1,613,998 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0654%	1,529
Remaining individualsnot grpmax-eligible	0.008%	12,497
Admixed American	0.00167%	60,002
South Asian	0.0011%	91,090

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: CLOCK
Protein: p.Met611Val
Coding: c.1831A>G
MANE Select: NM_004898
Type: single nucleotide variant
Location: chr4:55443758 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 61.90 · 2 PDB
Residue 611: the 'interaction with nr3c1' region

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

Similar variants

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
CLOCK p.Arg386Gln 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-met611val (accessed [today's date]).

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