Is CNOT3 p.Ser282Phe (c.845C>T) pathogenic?

CNOT3 p.Ser282Phe (c.845C>T) is classified Conflicting classifications of pathogenicity in CNOT3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-04-08). AlphaMissense: likely pathogenic (0.8126); Very rare (popmax 0.000724%, nfe); Associated with intellectual developmental disorder with speech delay, autism, and dysmorphic facies.

How common is CNOT3 p.Ser282Phe (c.845C>T) in the general population?

CNOT3 p.Ser282Phe (c.845C>T) is very rare (popmax 0.000724%, nfe) (gnomAD).

What do computational predictors say about CNOT3 p.Ser282Phe (c.845C>T)?

AlphaMissense predicts likely pathogenic (score 0.8126) — an in-silico prediction, not a clinical call.

CNOT3 p.Ser282Phe

Q: What condition is associated with CNOT3 p.Ser282Phe (c.845C>T)?

CNOT3 p.Ser282Phe (c.845C>T) is associated with intellectual developmental disorder with speech delay, autism, and dysmorphic facies (ClinVar).

c.845C>T · VCV4888435

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8126 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000724%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with speech delay, autism, and dysmorphic facies

Computational evidence

Protein change
AlphaMissense	0.8126	likely pathogenic
REVEL	0.139	moderately benign-leaning
SaProt	LLR -9.17	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 7,004 bp · p 0.37 · regional, not allelic
Overall
CADD	29.4	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 0.000724% European (non-Finnish) · 8/1,105,380 alleles

Filtering AF 0.000311% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000225%

Overall 0.000587% 9/1,531,962 alleles · very rare exomes 7/1,379,756 · genomes 2/152,206 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00168%	59,690
European (non-Finnish)grpmax	0.000724%	138,173

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser282Phe
Coding: c.845C>T
MANE Select: NM_014516
Type: single nucleotide variant
Location: chr19:54146608 (GRCh38)
Gene constraint: LOEUF 0.057 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.53 · 6 PDB
Residue 282: the 'disordered' region

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

Disease context

intellectual developmental disorder with speech delay, autism, and dysmorphic facies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNOT3 c.1904+2T>C Pathogenic/Likely pathogenic ★★ same condition
CNOT3 p.Arg697Ter Pathogenic ★★ same condition
CNOT3 p.Arg81Ser Likely pathogenic ★★ same condition
CNOT3 p.Arg96Ter Pathogenic/Likely pathogenic ★★ same condition
CNOT3 p.Thr86= Likely pathogenic ★★ same condition
CNOT3 c.483+6T>G Uncertain significance ★★ same condition
CNOT3 p.Arg665His Uncertain significance ★★ ⚠ same condition
CNOT3 p.Gln453Leu 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-ser282phe (accessed [today's date]).

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