Is CNOT6 p.Pro2Leu (c.5C>T) pathogenic?

CNOT6 p.Pro2Leu (c.5C>T) is classified Uncertain significance in CNOT6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-25). AlphaMissense: ambiguous (0.4319); Ultra-rare (popmax 0.0165%, mid).

How common is CNOT6 p.Pro2Leu (c.5C>T) in the general population?

CNOT6 p.Pro2Leu (c.5C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CNOT6 p.Pro2Leu (c.5C>T)?

AlphaMissense predicts ambiguous (score 0.4319) — an in-silico prediction, not a clinical call.

CNOT6 p.Pro2Leu

c.5C>T · rs772817399 · VCV3146631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4319 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4319	ambiguous
REVEL	0.273	benign-leaning
SaProt	LLR -6.96	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 38 kb · p 5.7e-08 · regional, not allelic
Overall
CADD	29.2	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 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.000697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000545%

Overall 0.001% 16/1,596,612 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
African / African-American	0.00134%	74,396
European (non-Finnish)	0.0012%	83,224

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.Pro2Leu
Coding: c.5C>T
MANE Select: NM_001370472
dbSNP: rs772817399
Type: single nucleotide variant
Location: chr5:180529281 (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

CCR4 p.Ala246Thr Uncertain significance ★ ⚠ same type
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-pro2leu (accessed [today's date]).

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