Is CNOT2 p.Ser405Phe (c.1214C>T) pathogenic?

CNOT2 p.Ser405Phe (c.1214C>T) is classified Uncertain significance in CNOT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-01). AlphaMissense: likely pathogenic (0.6489); Absent from gnomAD v4.1.

How common is CNOT2 p.Ser405Phe (c.1214C>T) in the general population?

CNOT2 p.Ser405Phe (c.1214C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNOT2 p.Ser405Phe (c.1214C>T)?

AlphaMissense predicts likely pathogenic (score 0.6489) — an in-silico prediction, not a clinical call.

CNOT2 p.Ser405Phe

c.1214C>T · VCV3373099

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6489 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6489	likely pathogenic
REVEL	0.304	indeterminate
SaProt	LLR -10.87	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 6,728 bp · p 6e-12 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: CNOT2
Protein: p.Ser405Phe
Coding: c.1214C>T
MANE Select: NM_014515
Type: single nucleotide variant
Location: chr12:70342142 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.35 · 4 PDB
Residue 405: a UniProt-annotated variant site (in idnadfs)

Full CNOT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNOT2 p.Arg183Gln Uncertain significance ★★ ⚠ same type
CNOT2 p.Tyr494Cys Uncertain significance ★★ ⚠ same type
CNOT2 p.Gly32Glu Likely benign ★★ same type
CNOT2 p.Met49Val Likely benign ★★ same type
CNOT2 c.49-2A>G Likely pathogenic ★ same type
CNOT2 p.Ser228Ter Pathogenic ★ same type
CNOT2 c.1179-10C>A Uncertain significance ★ same type
CNOT2 c.49-2A>C 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/cnot2-p-ser405phe (accessed [today's date]).

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