Is CNOT3 p.Pro235Ser (c.703C>T) pathogenic?

CNOT3 p.Pro235Ser (c.703C>T) is classified Uncertain significance in CNOT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-01). AlphaMissense: likely benign (0.3034); Very rare (popmax 0.000425%, nfe).

How common is CNOT3 p.Pro235Ser (c.703C>T) in the general population?

CNOT3 p.Pro235Ser (c.703C>T) is very rare (popmax 0.000425%, nfe) (gnomAD).

What do computational predictors say about CNOT3 p.Pro235Ser (c.703C>T)?

AlphaMissense predicts likely benign (score 0.3034) — an in-silico prediction, not a clinical call.

CNOT3 p.Pro235Ser

c.703C>T · VCV3682140

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3034 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000425%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3034	likely benign
REVEL	0.207	benign-leaning
SaProt	LLR -5.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.36	unconstrained · MANE · 233 bp · p 1.2e-07 · regional, not allelic
Overall
CADD	25.4	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

Grpmax group 0.000425% European (non-Finnish) · 5/1,177,368 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,610,744 alleles · very rare

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.Pro235Ser
Coding: c.703C>T
MANE Select: NM_014516
Type: single nucleotide variant
Location: chr19:54145817 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.53 · 6 PDB

Full CNOT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNOT3 c.1904+2T>C Pathogenic/Likely pathogenic ★★ same type
CNOT3 p.Arg697Ter Pathogenic ★★ same type
CNOT3 p.Arg81Ser Likely pathogenic ★★ same type
CNOT3 p.Arg96Ter Pathogenic/Likely pathogenic ★★ same type
CNOT3 p.Thr86= Likely pathogenic ★★ same type
CNOT3 c.1905-7C>G Uncertain significance ★★ same type
CNOT3 c.483+6T>G Uncertain significance ★★ same type
CNOT3 p.Ala376Thr 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/cnot3-p-pro235ser (accessed [today's date]).

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