Is CNOT1 p.Arg274Cys (c.820C>T) pathogenic?

CNOT1 p.Arg274Cys (c.820C>T) is classified Uncertain significance in CNOT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-09). AlphaMissense: ambiguous (0.3991); Very rare (popmax 0.0011%, sas); Associated with neurodevelopmental disorder.

What condition is associated with CNOT1 p.Arg274Cys (c.820C>T)?

CNOT1 p.Arg274Cys (c.820C>T) is associated with neurodevelopmental disorder (ClinVar).

How common is CNOT1 p.Arg274Cys (c.820C>T) in the general population?

CNOT1 p.Arg274Cys (c.820C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CNOT1 p.Arg274Cys (c.820C>T)?

AlphaMissense predicts ambiguous (score 0.3991) — an in-silico prediction, not a clinical call.

CNOT1 p.Arg274Cys

c.820C>T · rs1351476758 · VCV2627871

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.3991	ambiguous
REVEL	0.451	indeterminate
SaProt	LLR -12.79	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 43 kb · p 6e-23 · regional, not allelic
Overall
CADD	34.0	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 · 1/91,030 alleles

Overall 6.84e-05% 1/1,461,570 alleles · very rare

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.Arg274Cys
Coding: c.820C>T
MANE Select: NM_016284
dbSNP: rs1351476758
Type: single nucleotide variant
Location: chr16:58583169 (GRCh38)
Gene constraint: LOEUF 0.064 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.22 · 21 PDB
Residue 274: a UniProt-annotated variant site (in vibos); an α-helix

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

Disease context

neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNOT1 p.Arg274His Uncertain significance ★ ⚠ same residue
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.Ala1503Thr 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-arg274cys (accessed [today's date]).

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