Is CNOT2 p.Pro136Ser (c.406C>T) pathogenic?

CNOT2 p.Pro136Ser (c.406C>T) is classified Uncertain significance in CNOT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-15). AlphaMissense: likely benign (0.0506); Absent from gnomAD v4.1; Associated with intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies.

How common is CNOT2 p.Pro136Ser (c.406C>T) in the general population?

CNOT2 p.Pro136Ser (c.406C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNOT2 p.Pro136Ser (c.406C>T)?

AlphaMissense predicts likely benign (score 0.0506) — an in-silico prediction, not a clinical call.

CNOT2 p.Pro136Ser

Q: What condition is associated with CNOT2 p.Pro136Ser (c.406C>T)?

CNOT2 p.Pro136Ser (c.406C>T) is associated with intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (ClinVar).

c.406C>T · rs2499107829 · VCV2440168

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0506 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies

Computational evidence

Protein change
AlphaMissense	0.0506	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -5.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 52 kb · p 3.3e-07 · regional, not allelic
Overall
CADD	20.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CNOT2
Protein: p.Pro136Ser
Coding: c.406C>T
MANE Select: NM_014515
dbSNP: rs2499107829
Type: single nucleotide variant
Location: chr12:70330306 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 60.35 · 4 PDB

Full CNOT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNOT2 p.Tyr494Cys Uncertain significance ★★ same condition
CNOT2 p.Gln411Arg Uncertain significance ★ ⚠ same condition
CNOT2 p.Lys316Ter Pathogenic same condition
CNOT2 p.Gln457fs Likely pathogenic ★ same condition
CNOT2 p.His526fs Likely pathogenic ★ same condition
CNOT2 p.Leu376fs Likely pathogenic ★ same condition
CNOT2 p.Arg183Gln Uncertain significance ★★ ⚠ same type
CNOT2 p.Gly32Glu Likely benign ★★ 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/cnot2-p-pro136ser (accessed [today's date]).

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