Is CLOCK p.Arg387Gln (c.1160G>A) pathogenic?

CLOCK p.Arg387Gln (c.1160G>A) is classified Uncertain significance in CLOCK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely benign (0.1101); Rare (popmax 0.114%, sas).

How common is CLOCK p.Arg387Gln (c.1160G>A) in the general population?

CLOCK p.Arg387Gln (c.1160G>A) is rare (popmax 0.114%, sas) (gnomAD).

What do computational predictors say about CLOCK p.Arg387Gln (c.1160G>A)?

AlphaMissense predicts likely benign (score 0.1101) — an in-silico prediction, not a clinical call.

CLOCK p.Arg387Gln

c.1160G>A · VCV4003789

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1101 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.114%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1101	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -10.36	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 18 kb · p 0.11 · regional, not allelic
Overall
CADD	26.9	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 0.114% South Asian · 104/90,960 alleles

Filtering AF 0.0965% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0898%

Overall 0.0067% 108/1,612,654 alleles · rare exomes 105/1,460,520 · genomes 3/152,134 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.114%	875
Admixed American	0.00167%	59,968
Remaining individualsnot grpmax-eligible	0.0016%	62,412
African / African-American	0.00134%	74,894
European (non-Finnish)	8.48e-05%	1,179,135

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.Arg387Gln
Coding: c.1160G>A
MANE Select: NM_004898
Type: single nucleotide variant
Location: chr4:55453100 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 61.90 · 2 PDB
Residue 387: 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-arg387gln (accessed [today's date]).

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