Is CLOCK p.Ile369Val (c.1105A>G) pathogenic?

CLOCK p.Ile369Val (c.1105A>G) is classified Uncertain significance in CLOCK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-27). AlphaMissense: ambiguous (0.3435); Very rare (popmax 8.49e-05%, nfe).

How common is CLOCK p.Ile369Val (c.1105A>G) in the general population?

CLOCK p.Ile369Val (c.1105A>G) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about CLOCK p.Ile369Val (c.1105A>G)?

AlphaMissense predicts ambiguous (score 0.3435) — an in-silico prediction, not a clinical call.

CLOCK p.Ile369Val

c.1105A>G · VCV4654509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3435 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3435	ambiguous
REVEL	0.188	benign-leaning
SaProt	LLR -11.01	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 2,875 bp · p 0.0008 · regional, not allelic
Overall
CADD	26.1	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 8.49e-05% European (non-Finnish) · 1/1,177,828 alleles

Overall 6.86e-05% 1/1,458,648 alleles · very rare

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.Ile369Val
Coding: c.1105A>G
MANE Select: NM_004898
Type: single nucleotide variant
Location: chr4:55453702 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 61.90 · 2 PDB
Residue 369: the pac domain

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-ile369val (accessed [today's date]).

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