Is CNOT3 p.Pro320Leu (c.959C>T) pathogenic?

CNOT3 p.Pro320Leu (c.959C>T) is classified Uncertain significance in CNOT3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-08). AlphaMissense: likely benign (0.0575); Very rare (popmax 0.00807%, afr); Associated with Inborn genetic diseases.

What condition is associated with CNOT3 p.Pro320Leu (c.959C>T)?

CNOT3 p.Pro320Leu (c.959C>T) is associated with Inborn genetic diseases, intellectual disability (ClinVar).

How common is CNOT3 p.Pro320Leu (c.959C>T) in the general population?

CNOT3 p.Pro320Leu (c.959C>T) is very rare (popmax 0.00807%, afr) (gnomAD).

What do computational predictors say about CNOT3 p.Pro320Leu (c.959C>T)?

AlphaMissense predicts likely benign (score 0.0575) — an in-silico prediction, not a clinical call.

CNOT3 p.Pro320Leu

c.959C>T · rs190206269 · VCV975368

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0575 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00807%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0575	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -8.37	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 3.2	GERP -0.13, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 7,004 bp · p 0.37 · regional, not allelic
Overall
CADD	23.7	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

Grpmax group 0.00807% African / African-American · 6/74,306 alleles

Filtering AF 0.00381% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00348%

Overall 0.00434% 69/1,591,372 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00807%	12,384
European (non-Finnish)	0.00488%	20,511
Remaining individualsnot grpmax-eligible	0.00325%	30,751
South Asian	0.00228%	43,941
East Asian	0.00227%	44,016
Admixed American	0.00176%	56,928

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: CNOT3
Protein: p.Pro320Leu
Coding: c.959C>T
MANE Select: NM_014516
dbSNP: rs190206269
Type: single nucleotide variant
Location: chr19:54148212 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.53 · 6 PDB
Residue 320: the 'disordered' region

Full CNOT3 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

Also linked: intellectual disability

Similar variants

CNOT3 p.Ala438Val Uncertain significance ★★ ⚠ same condition
CNOT3 p.Arg290Cys Uncertain significance ★★ ⚠ same condition
CNOT3 p.Glu533Gln Uncertain significance ★★ ⚠ same condition
CNOT3 p.Gly405Ser Uncertain significance ★★ ⚠ same condition
CNOT3 p.Met182Val Uncertain significance ★★ ⚠ same condition
CNOT3 p.Pro244Ala Uncertain significance ★★ ⚠ same condition
CNOT3 p.Pro510Ser Uncertain significance ★★ ⚠ same condition
CNOT3 p.Pro579Leu 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/cnot3-p-pro320leu (accessed [today's date]).

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