Is CNOT1 p.Ile992Val (c.2974A>G) pathogenic?

CNOT1 p.Ile992Val (c.2974A>G) is classified Uncertain significance in CNOT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). AlphaMissense: likely benign (0.1235); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CNOT1 p.Ile992Val (c.2974A>G)?

CNOT1 p.Ile992Val (c.2974A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CNOT1 p.Ile992Val (c.2974A>G) in the general population?

CNOT1 p.Ile992Val (c.2974A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNOT1 p.Ile992Val (c.2974A>G)?

AlphaMissense predicts likely benign (score 0.1235) — an in-silico prediction, not a clinical call.

CNOT1 p.Ile992Val

c.2974A>G · VCV4004348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1235 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1235	likely benign
REVEL	0.166	moderately benign-leaning
SaProt	LLR -6.28	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 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 2,182 bp · p 0.15 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CNOT1
Protein: p.Ile992Val
Coding: c.2974A>G
MANE Select: NM_016284
Type: single nucleotide variant
Location: chr16:58551816 (GRCh38)
Gene constraint: LOEUF 0.064 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.22 · 21 PDB
Residue 992: an α-helix; the 'interaction with zfp36' region; 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 p.Ile992Thr Uncertain significance ★ ⚠ same residue
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

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-ile992val (accessed [today's date]).

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