Is CLOCK p.Gly673Arg (c.2017G>A) pathogenic?

CLOCK p.Gly673Arg (c.2017G>A) is classified Uncertain significance in CLOCK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-28). AlphaMissense: ambiguous (0.4333); Ultra-rare (popmax 0.0258%, nfe).

How common is CLOCK p.Gly673Arg (c.2017G>A) in the general population?

CLOCK p.Gly673Arg (c.2017G>A) is ultra-rare (popmax 0.0258%, nfe) (gnomAD).

What do computational predictors say about CLOCK p.Gly673Arg (c.2017G>A)?

AlphaMissense predicts ambiguous (score 0.4333) — an in-silico prediction, not a clinical call.

CLOCK p.Gly673Arg

c.2017G>A · rs145873359 · VCV2456067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4333 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0258%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4333	ambiguous
REVEL	0.122	moderately benign-leaning
SaProt	LLR -8.24	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 18 kb · p 0.11 · regional, not allelic
Overall
CADD	23.6	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 0.0258% European (non-Finnish) · 304/1,179,070 alleles

Filtering AF 0.0233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0224%

Overall 0.0213% 342/1,608,852 alleles · ultra-rare exomes 308/1,461,832 · genomes 34/147,020 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0258%	3,879
African / African-American	0.0247%	4,057
Remaining individualsnot grpmax-eligible	0.00962%	10,395
East Asian	0.00895%	11,173
Admixed American	0.00845%	11,834
Finnishnot grpmax-eligible	0.00788%	12,683

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.Gly673Arg
Coding: c.2017G>A
MANE Select: NM_004898
dbSNP: rs145873359
Type: single nucleotide variant
Location: chr4:55442520 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 61.90 · 2 PDB
Residue 673: 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-gly673arg (accessed [today's date]).

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