Is CLOCK p.Arg82Gln (c.245G>A) pathogenic?

CLOCK p.Arg82Gln (c.245G>A) is classified Uncertain significance in CLOCK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-28). AlphaMissense: likely benign (0.1353); Rare (popmax 0.112%, afr).

How common is CLOCK p.Arg82Gln (c.245G>A) in the general population?

CLOCK p.Arg82Gln (c.245G>A) is rare (popmax 0.112%, afr) (gnomAD).

What do computational predictors say about CLOCK p.Arg82Gln (c.245G>A)?

AlphaMissense predicts likely benign (score 0.1353) — an in-silico prediction, not a clinical call.

CLOCK p.Arg82Gln

c.245G>A · rs140094629 · VCV2396655

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1353 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.112%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1353	likely benign
REVEL	0.481	indeterminate
SaProt	LLR -8.70	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.8, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 24 kb · p 0.0017 · regional, not allelic
Overall
CADD	23.7	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 0.112% African / African-American · 84/74,852 alleles

Filtering AF 0.0928% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0857%

Overall 0.00819% 132/1,612,222 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.112%	891
Middle Eastern	0.104%	960
Admixed American	0.025%	3,995
Remaining individualsnot grpmax-eligible	0.024%	4,159
South Asian	0.0011%	90,964
European (non-Finnish)	0.000933%	107,198

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.Arg82Gln
Coding: c.245G>A
MANE Select: NM_004898
dbSNP: rs140094629
Type: single nucleotide variant
Location: chr4:55478826 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 61.90 · 2 PDB
Residue 82: the bhlh domain; an α-helix

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-arg82gln (accessed [today's date]).

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