Is CLOCK p.Leu118Val (c.352C>G) pathogenic?

CLOCK p.Leu118Val (c.352C>G) is classified Uncertain significance in CLOCK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-16). AlphaMissense: ambiguous (0.3681); Absent from gnomAD v4.1.

How common is CLOCK p.Leu118Val (c.352C>G) in the general population?

CLOCK p.Leu118Val (c.352C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLOCK p.Leu118Val (c.352C>G)?

AlphaMissense predicts ambiguous (score 0.3681) — an in-silico prediction, not a clinical call.

CLOCK p.Leu118Val

c.352C>G · rs968471712 · VCV2261852

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3681 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.3681	ambiguous
REVEL	0.348	indeterminate
SaProt	LLR -9.01	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 24 kb · p 0.0017 · regional, not allelic
Overall
CADD	28.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLOCK
Protein: p.Leu118Val
Coding: c.352C>G
MANE Select: NM_004898
dbSNP: rs968471712
Type: single nucleotide variant
Location: chr4:55470803 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 61.90 · 2 PDB
Residue 118: the pas 1 domain; an α-helix

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-leu118val (accessed [today's date]).

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