Is CLOCK p.His525Gln (c.1575T>A) pathogenic?

CLOCK p.His525Gln (c.1575T>A) is classified Uncertain significance in CLOCK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-21). AlphaMissense: ambiguous (0.4201); Very rare (popmax 0.00517%, nfe).

How common is CLOCK p.His525Gln (c.1575T>A) in the general population?

CLOCK p.His525Gln (c.1575T>A) is very rare (popmax 0.00517%, nfe) (gnomAD).

What do computational predictors say about CLOCK p.His525Gln (c.1575T>A)?

AlphaMissense predicts ambiguous (score 0.4201) — an in-silico prediction, not a clinical call.

CLOCK p.His525Gln

c.1575T>A · VCV3493841

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4201 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4201	ambiguous
REVEL	0.15	moderately benign-leaning
SaProt	LLR -3.96	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 0.18, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 18 kb · p 0.11 · regional, not allelic
Overall
CADD	19.29	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 0.00517% European (non-Finnish) · 61/1,179,998 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00397% 64/1,613,926 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00517%	19,344
Admixed American	0.00333%	30,005
Finnishnot grpmax-eligible	0.00156%	64,010

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.His525Gln
Coding: c.1575T>A
MANE Select: NM_004898
Type: single nucleotide variant
Location: chr4:55444750 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 61.90 · 2 PDB
Residue 525: the 'interaction with nr3c1' region; the 'interaction with sirt1' region; the 'implicated in the circadian rhythmicity' 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-his525gln (accessed [today's date]).

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