Is CNOT6 p.Arg12Trp (c.34C>T) pathogenic?

CNOT6 p.Arg12Trp (c.34C>T) is classified Uncertain significance in CNOT6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-20). AlphaMissense: likely pathogenic (0.7527); Very rare (popmax 0.00223%, eas).

How common is CNOT6 p.Arg12Trp (c.34C>T) in the general population?

CNOT6 p.Arg12Trp (c.34C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CNOT6 p.Arg12Trp (c.34C>T)?

AlphaMissense predicts likely pathogenic (score 0.7527) — an in-silico prediction, not a clinical call.

CNOT6 p.Arg12Trp

c.34C>T · rs1278199401 · VCV3146630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7527 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7527	likely pathogenic
REVEL	0.283	benign-leaning
SaProt	LLR -12.88	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 38 kb · p 5.7e-08 · regional, not allelic
Overall
CADD	33.0	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 0.00223% East Asian · 1/44,870 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000372% 6/1,613,110 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,870
South Asian	0.0022%	45,489
African / African-American	0.00134%	74,838
European (non-Finnish)	0.00017%	589,727

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: CNOT6
Protein: p.Arg12Trp
Coding: c.34C>T
MANE Select: NM_001370472
dbSNP: rs1278199401
Type: single nucleotide variant
Location: chr5:180529310 (GRCh38)
Gene constraint: LOEUF 0.32 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.51 · 1 PDB

Full CNOT6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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CCR4 p.Ala246Val Uncertain significance ★ ⚠ same type
CCR4 p.Arg147Trp Uncertain significance ★ ⚠ same type
CCR4 p.Cys178Arg Uncertain significance ★ ⚠ same type
CCR4 p.Cys329Gly Uncertain significance ★ ⚠ same type
CCR4 p.Gln230Lys Uncertain significance ★ ⚠ same type
CCR4 p.His357Arg Uncertain significance ★ ⚠ same type
CCR4 p.Ile15Val 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/cnot6-p-arg12trp (accessed [today's date]).

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