Is CNOT2 p.Met49Val (c.145A>G) pathogenic?

CNOT2 p.Met49Val (c.145A>G) is classified Likely benign in CNOT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-01). AlphaMissense: likely benign (0.0569); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with CNOT2 p.Met49Val (c.145A>G)?

CNOT2 p.Met49Val (c.145A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CNOT2 p.Met49Val (c.145A>G) in the general population?

CNOT2 p.Met49Val (c.145A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CNOT2 p.Met49Val (c.145A>G)?

AlphaMissense predicts likely benign (score 0.0569) — an in-silico prediction, not a clinical call.

CNOT2 p.Met49Val

c.145A>G · rs138621902 · VCV2672511

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0569 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0569	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -6.84	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 4.2	GERP -0.67, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 52 kb · p 3.3e-07 · regional, not allelic
Overall
CADD	20.9	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.0025% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0022%

Overall 0.00313% 50/1,599,708 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Admixed American	0.00501%	19,957
European (non-Finnish)	0.00334%	29,937
Finnishnot grpmax-eligible	0.00313%	31,960
African / African-American	0.00268%	37,293
East Asian	0.00223%	44,786
South Asian	0.00221%	45,272

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.Met49Val
Coding: c.145A>G
MANE Select: NM_014515
dbSNP: rs138621902
Type: single nucleotide variant
Location: chr12:70310991 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNOT2 p.Arg183Gln Uncertain significance ★★ ⚠ same condition
CNOT2 p.Gly32Glu Likely benign ★★ same condition
CNOT2 p.Ser228Ter Pathogenic ★ same condition
CNOT2 p.Ala253Gly Uncertain significance ★ ⚠ same condition
CNOT2 p.Ala266Gly Uncertain significance ★ ⚠ same condition
CNOT2 p.Arg236Gly Uncertain significance ★ ⚠ same condition
CNOT2 p.Arg53Gln Uncertain significance ★ ⚠ same condition
CNOT2 p.Asn237Lys 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/cnot2-p-met49val (accessed [today's date]).

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