Is CNOT1 p.Pro578Ala (c.1732C>G) pathogenic?

CNOT1 p.Pro578Ala (c.1732C>G) is classified Uncertain significance in CNOT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-22). AlphaMissense: likely pathogenic (0.6467); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with CNOT1 p.Pro578Ala (c.1732C>G)?

CNOT1 p.Pro578Ala (c.1732C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CNOT1 p.Pro578Ala (c.1732C>G) in the general population?

CNOT1 p.Pro578Ala (c.1732C>G) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about CNOT1 p.Pro578Ala (c.1732C>G)?

AlphaMissense predicts likely pathogenic (score 0.6467) — an in-silico prediction, not a clinical call.

CNOT1 p.Pro578Ala

c.1732C>G · VCV4838171

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6467 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6467	likely pathogenic
REVEL	0.388	indeterminate
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 43 kb · p 6e-23 · regional, not allelic
Overall
CADD	24.5	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 0.00534% African / African-American · 4/74,920 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00031% 5/1,613,932 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,730
Finnishnot grpmax-eligible	0.00156%	63,992

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.Pro578Ala
Coding: c.1732C>G
MANE Select: NM_016284
Type: single nucleotide variant
Location: chr16:58575102 (GRCh38)
Gene constraint: LOEUF 0.064 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.22 · 21 PDB
Residue 578: a UniProt-annotated variant site (in vibos)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNOT1 c.5895+4T>C Uncertain significance ★★ same condition
CNOT1 p.Ala1604Gly Uncertain significance ★★ ⚠ same condition
CNOT1 p.Arg211Cys Uncertain significance ★★ ⚠ same condition
CNOT1 p.Arg369Cys Uncertain significance ★★ ⚠ same condition
CNOT1 p.Asn1162Thr Uncertain significance ★★ ⚠ same condition
CNOT1 p.Asn1295Ser Uncertain significance ★★ ⚠ same condition
CNOT1 p.Asn2199Lys Uncertain significance ★★ ⚠ same condition
CNOT1 p.Asn349Ser Uncertain significance ★★ ⚠ same condition

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-pro578ala (accessed [today's date]).

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