Is CLOCK p.Asp151His (c.451G>C) pathogenic?

CLOCK p.Asp151His (c.451G>C) is classified Uncertain significance in CLOCK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-21). AlphaMissense: ambiguous (0.4504); Very rare (popmax 0.00348%, nfe).

How common is CLOCK p.Asp151His (c.451G>C) in the general population?

CLOCK p.Asp151His (c.451G>C) is very rare (popmax 0.00348%, nfe) (gnomAD).

What do computational predictors say about CLOCK p.Asp151His (c.451G>C)?

AlphaMissense predicts ambiguous (score 0.4504) — an in-silico prediction, not a clinical call.

CLOCK p.Asp151His

c.451G>C · rs375936156 · VCV2379503

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4504 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00348%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4504	ambiguous
REVEL	0.431	indeterminate
SaProt	LLR -9.06	tolerated
Splicing
SpliceAI	Δ0.24	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 24 kb · p 0.0017 · regional, not allelic
Overall
CADD	29.8	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 0.00348% European (non-Finnish) · 41/1,177,118 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00273% 44/1,609,558 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00348%	28,710
Remaining individualsnot grpmax-eligible	0.00321%	31,135
African / African-American	0.00134%	74,756

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.Asp151His
Coding: c.451G>C
MANE Select: NM_004898
dbSNP: rs375936156
Type: single nucleotide variant
Location: chr4:55463793 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 61.90 · 2 PDB
Residue 151: the pas 1 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-asp151his (accessed [today's date]).

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