Is CNOT4 p.Asp281Tyr (c.841G>T) pathogenic?

CNOT4 p.Asp281Tyr (c.841G>T) is classified Uncertain significance in CNOT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely benign (0.2508); Absent from gnomAD v4.1.

How common is CNOT4 p.Asp281Tyr (c.841G>T) in the general population?

CNOT4 p.Asp281Tyr (c.841G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNOT4 p.Asp281Tyr (c.841G>T)?

AlphaMissense predicts likely benign (score 0.2508) — an in-silico prediction, not a clinical call.

CNOT4 p.Asp281Tyr

c.841G>T · VCV4654973

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2508 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2508	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -7.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.23	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 0.13 · regional, not allelic
Overall
CADD	27.4	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: CNOT4
Protein: p.Asp281Tyr
Coding: c.841G>T
MANE Select: NM_001190850
Type: single nucleotide variant
Location: chr7:135398207 (GRCh38)
Gene constraint: LOEUF 0.236 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.54 · 2 PDB
Residue 281: the 'disordered' region

Full CNOT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNOT4 p.Ala101Ser Uncertain significance ★ ⚠ same type
CNOT4 p.Ala459Thr Uncertain significance ★ ⚠ same type
CNOT4 p.Ala583Thr Uncertain significance ★ same type
CNOT4 p.Ala587Val Uncertain significance ★ same type
CNOT4 p.Ala649Pro Uncertain significance ★ same type
CNOT4 p.Ala669Thr Uncertain significance ★ same type
CNOT4 p.Arg323Gln Uncertain significance ★ ⚠ same type
CNOT4 p.Arg342His 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/cnot4-p-asp281tyr (accessed [today's date]).

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