Is CNOT1 p.Pro2143= (c.6429C>T) pathogenic?

CNOT1 p.Pro2143= (c.6429C>T) is classified Likely benign in CNOT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-11). Ultra-rare (popmax 0.016%, afr).

How common is CNOT1 p.Pro2143= (c.6429C>T) in the general population?

CNOT1 p.Pro2143= (c.6429C>T) is ultra-rare (popmax 0.016%, afr) (gnomAD).

CNOT1 p.Pro2143=

c.6429C>T · rs377330465 · VCV2646572

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.38	GERP -4.6, phastCons 0.23
Overall
CADD	3.606	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% African / African-American · 12/74,824 alleles

Filtering AF 0.00923% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00682% 110/1,613,210 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,235
European (non-Finnish)	0.0078%	12,820
Remaining individualsnot grpmax-eligible	0.0064%	15,619
Admixed American	0.00167%	59,958
Finnishnot grpmax-eligible	0.00156%	63,994

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: CNOT1
Protein: p.Pro2143=
Coding: c.6429C>T
MANE Select: NM_016284
dbSNP: rs377330465
Type: single nucleotide variant
Location: chr16:58528499 (GRCh38)
Gene constraint: LOEUF 0.064 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.22 · 21 PDB
Residue 2143: an α-helix; a UniProt-annotated variant site (in vibos)

Full CNOT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNOT1 p.Pro2143Arg Uncertain significance ★ ⚠ same residue
CNOT1 p.Pro2143Ser Uncertain significance ★ ⚠ same residue
CNOT1 c.434-2A>G Pathogenic ★★ same type
CNOT1 p.Arg26Ter Pathogenic/Likely pathogenic ★★ same type
CNOT1 p.Arg535Cys Pathogenic ★★ same type
CNOT1 c.310-3C>G Uncertain significance ★★ same type
CNOT1 c.5895+4T>C Uncertain significance ★★ same type
CNOT1 p.Ala1368Val 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/cnot1-p-pro2143 (accessed [today's date]).

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