Is CNOT3 p.Arg750Pro (c.2249G>C) pathogenic?

CNOT3 p.Arg750Pro (c.2249G>C) is classified Uncertain significance in CNOT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-29). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CNOT3 p.Arg750Pro (c.2249G>C)?

CNOT3 p.Arg750Pro (c.2249G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CNOT3 p.Arg750Pro (c.2249G>C) in the general population?

CNOT3 p.Arg750Pro (c.2249G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNOT3 p.Arg750Pro (c.2249G>C)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

CNOT3 p.Arg750Pro

c.2249G>C · rs2075353663 · VCV3146619

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,601,444)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 10% in CNOT3
REVEL	0.448	indeterminate
SaProt	LLR -10.69	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 7.5	GERP 0.53, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 1,572 bp · p 2.5e-06 · regional, not allelic
Overall
CADD	27.9	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

No allele count reported in gnomAD v4.1 (AN 1,601,444). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CNOT3
Protein: p.Arg750Pro
Coding: c.2249G>C
MANE Select: NM_014516
dbSNP: rs2075353663
Type: single nucleotide variant
Location: chr19:54155394 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.53 · 6 PDB
Residue 750: the 'repressor domain' region; a UniProt-annotated variant site (in iddsadf)

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

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.Pro320Leu Uncertain significance ★★ ⚠ same condition
CNOT3 p.Pro510Ser 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-arg750pro (accessed [today's date]).

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