Is CLOCK p.Gly235Glu (c.704G>A) pathogenic?

CLOCK p.Gly235Glu (c.704G>A) is classified Likely benign in CLOCK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-14). AlphaMissense: likely benign (0.1391); Rare (popmax 0.291%, afr).

How common is CLOCK p.Gly235Glu (c.704G>A) in the general population?

CLOCK p.Gly235Glu (c.704G>A) is rare (popmax 0.291%, afr) (gnomAD).

What do computational predictors say about CLOCK p.Gly235Glu (c.704G>A)?

AlphaMissense predicts likely benign (score 0.1391) — an in-silico prediction, not a clinical call.

CLOCK p.Gly235Glu

c.704G>A · rs138755597 · VCV726740

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1391 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.291%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1391	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -6.09	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 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 24 kb · p 0.0017 · regional, not allelic
Overall
CADD	23.1	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

Grpmax group 0.291% African / African-American · 218/74,994 alleles

Filtering AF 0.259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.247%

Overall 0.0159% 257/1,613,794 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.291%	344
Admixed American	0.0417%	2,400
Remaining individualsnot grpmax-eligible	0.0176%	5,681
European (non-Finnish)	0.000254%	393,277

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.Gly235Glu
Coding: c.704G>A
MANE Select: NM_004898
dbSNP: rs138755597
Type: single nucleotide variant
Location: chr4:55458980 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 61.90 · 2 PDB

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 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
CLOCK p.Arg387Gln 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-gly235glu (accessed [today's date]).

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