Is CNOT2 p.Met134Val (c.400A>G) pathogenic?

CNOT2 p.Met134Val (c.400A>G) is classified Uncertain significance in CNOT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28). AlphaMissense: likely benign (0.0688); Ultra-rare (popmax 0.05%, mid).

How common is CNOT2 p.Met134Val (c.400A>G) in the general population?

CNOT2 p.Met134Val (c.400A>G) is ultra-rare (popmax 0.05%, mid) (gnomAD).

What do computational predictors say about CNOT2 p.Met134Val (c.400A>G)?

AlphaMissense predicts likely benign (score 0.0688) — an in-silico prediction, not a clinical call.

CNOT2 p.Met134Val

c.400A>G · VCV3896585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0688 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.05%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0688	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 52 kb · p 3.3e-07 · regional, not allelic
Overall
CADD	23.7	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 0.05% Middle Eastern · 3/5,998 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00726%

Overall 0.00107% 17/1,590,990 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.05%	1,999
South Asian	0.00447%	22,354
Admixed American	0.00171%	58,568
African / African-American	0.00135%	74,192
European (non-Finnish)	0.000688%	145,386

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.Met134Val
Coding: c.400A>G
MANE Select: NM_014515
Type: single nucleotide variant
Location: chr12:70330300 (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

Similar variants

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 c.49-2A>G Likely pathogenic ★ 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-met134val (accessed [today's date]).

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