Is CLOCK p.Pro456Leu (c.1367C>T) pathogenic?

CLOCK p.Pro456Leu (c.1367C>T) is classified Likely benign in CLOCK (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-15). AlphaMissense: likely benign (0.0707); Rare (popmax 0.562%, sas).

How common is CLOCK p.Pro456Leu (c.1367C>T) in the general population?

CLOCK p.Pro456Leu (c.1367C>T) is rare (popmax 0.562%, sas) (gnomAD).

What do computational predictors say about CLOCK p.Pro456Leu (c.1367C>T)?

AlphaMissense predicts likely benign (score 0.0707) — an in-silico prediction, not a clinical call.

CLOCK p.Pro456Leu

c.1367C>T · rs578243815 · VCV722817

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0707 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.562%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0707	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -6.88	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 7.4	GERP 0.65, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 18 kb · p 0.11 · regional, not allelic
Overall
CADD	22.2	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 0.562% South Asian · 512/91,064 alleles

Filtering AF 0.522% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.506%

Overall 0.0395% 638/1,613,888 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.562%	178
Remaining individualsnot grpmax-eligible	0.048%	2,083
Middle Eastern	0.0165%	6,060
East Asian	0.0112%	8,968
European (non-Finnish)	0.0072%	13,881
African / African-American	0.00533%	18,751
Admixed American	0.00167%	60,014

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.Pro456Leu
Coding: c.1367C>T
MANE Select: NM_004898
dbSNP: rs578243815
Type: single nucleotide variant
Location: chr4:55449478 (GRCh38)
Gene constraint: LOEUF 0.496 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 61.90 · 2 PDB
Residue 456: the 'interaction with nr3c1' region; the 'disordered' region; the 'interaction with sirt1' 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-pro456leu (accessed [today's date]).

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