Is CNOT2 p.Met89Thr (c.266T>C) pathogenic?

CNOT2 p.Met89Thr (c.266T>C) is classified Uncertain significance in CNOT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.2678); Ultra-rare (popmax 0.0165%, nfe); Associated with ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder.

How common is CNOT2 p.Met89Thr (c.266T>C) in the general population?

CNOT2 p.Met89Thr (c.266T>C) is ultra-rare (popmax 0.0165%, nfe) (gnomAD).

What do computational predictors say about CNOT2 p.Met89Thr (c.266T>C)?

AlphaMissense predicts likely benign (score 0.2678) — an in-silico prediction, not a clinical call.

CNOT2 p.Met89Thr

Q: What condition is associated with CNOT2 p.Met89Thr (c.266T>C)?

CNOT2 p.Met89Thr (c.266T>C) is associated with ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder (ClinVar).

c.266T>C · VCV4278469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2678 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder

Computational evidence

Protein change
AlphaMissense	0.2678	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -7.33	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 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 52 kb · p 3.3e-07 · regional, not allelic
Overall
CADD	24.0	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 0.0165% European (non-Finnish) · 185/1,119,602 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.0144% 201/1,395,230 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0165%	6,052
Remaining individualsnot grpmax-eligible	0.0116%	8,599
South Asian	0.00558%	17,928
African / African-American	0.00409%	24,461
East Asian	0.00225%	44,452

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: CNOT2
Protein: p.Met89Thr
Coding: c.266T>C
MANE Select: NM_014515
Type: single nucleotide variant
Location: chr12:70329450 (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

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNOT2 c.49-2A>G Likely pathogenic ★ same condition
CNOT2 p.Arg183Gln Uncertain significance ★★ ⚠ same type
CNOT2 p.Tyr494Cys Uncertain significance ★★ ⚠ same type
CNOT2 p.Gly32Glu Likely benign ★★ same type
CNOT2 p.Met49Val Likely benign ★★ same type
CNOT2 p.Ser228Ter Pathogenic ★ same type
CNOT2 c.1179-10C>A Uncertain significance ★ same type
CNOT2 c.49-2A>C 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/cnot2-p-met89thr (accessed [today's date]).

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