Is CNOT1 p.Ala1503Thr (c.4507G>A) pathogenic?

CNOT1 p.Ala1503Thr (c.4507G>A) is classified Uncertain significance in CNOT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-22). AlphaMissense: likely pathogenic (0.8822); Very rare (popmax 0.0011%, sas).

How common is CNOT1 p.Ala1503Thr (c.4507G>A) in the general population?

CNOT1 p.Ala1503Thr (c.4507G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CNOT1 p.Ala1503Thr (c.4507G>A)?

AlphaMissense predicts likely pathogenic (score 0.8822) — an in-silico prediction, not a clinical call.

CNOT1 p.Ala1503Thr

c.4507G>A · VCV3366670

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8822	likely pathogenic
REVEL	0.488	indeterminate
SaProt	LLR -9.96	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 3,135 bp · p 1.4e-10 · regional, not allelic
Overall
CADD	31.0	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 0.0011% South Asian · 1/90,770 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000208% 3/1,441,726 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,770
European (non-Finnish)	0.000172%	583,043

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: CNOT1
Protein: p.Ala1503Thr
Coding: c.4507G>A
MANE Select: NM_016284
Type: single nucleotide variant
Location: chr16:58542496 (GRCh38)
Gene constraint: LOEUF 0.064 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.22 · 21 PDB
Residue 1503: an α-helix; a UniProt-annotated variant site (in vibos); the 'interaction with cnot6, cnot6l, cnot7 and cnot8' region

Full CNOT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNOT1 c.434-2A>G Pathogenic ★★ same type
CNOT1 p.Arg26Ter Pathogenic/Likely pathogenic ★★ same type
CNOT1 p.Arg535Cys Pathogenic ★★ same type
CNOT1 c.310-3C>G Uncertain significance ★★ same type
CNOT1 c.5895+4T>C Uncertain significance ★★ same type
CNOT1 p.Ala1368Val Uncertain significance ★★ ⚠ same type
CNOT1 p.Ala1604Gly Uncertain significance ★★ ⚠ same type
CNOT1 p.Ala798Thr 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/cnot1-p-ala1503thr (accessed [today's date]).

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