Is CNOT1 p.Ile613Thr (c.1838T>C) pathogenic?

CNOT1 p.Ile613Thr (c.1838T>C) is classified Uncertain significance in CNOT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely pathogenic (0.9027); Very rare (popmax 0.0058%, amr); Associated with Inborn genetic diseases.

What condition is associated with CNOT1 p.Ile613Thr (c.1838T>C)?

CNOT1 p.Ile613Thr (c.1838T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CNOT1 p.Ile613Thr (c.1838T>C) in the general population?

CNOT1 p.Ile613Thr (c.1838T>C) is very rare (popmax 0.0058%, amr) (gnomAD).

What do computational predictors say about CNOT1 p.Ile613Thr (c.1838T>C)?

AlphaMissense predicts likely pathogenic (score 0.9027) — an in-silico prediction, not a clinical call.

CNOT1 p.Ile613Thr

c.1838T>C · rs777979058 · VCV2307781

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9027 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0058%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9027	likely pathogenic
REVEL	0.472	indeterminate
SaProt	LLR -10.58	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 43 kb · p 6e-23 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0058% Admixed American · 3/51,696 alleles

Filtering AF 0.00154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000827%

Overall 0.000416% 6/1,441,872 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0058%	17,232
East Asian	0.00223%	44,838
European (non-Finnish)	0.00017%	587,945

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.Ile613Thr
Coding: c.1838T>C
MANE Select: NM_016284
dbSNP: rs777979058
Type: single nucleotide variant
Location: chr16:58574750 (GRCh38)
Gene constraint: LOEUF 0.064 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.22 · 21 PDB
Residue 613: an α-helix; a UniProt-annotated variant site (in vibos)

Full CNOT1 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

CNOT1 c.5895+4T>C Uncertain significance ★★ same condition
CNOT1 p.Ala1604Gly Uncertain significance ★★ ⚠ same condition
CNOT1 p.Arg211Cys Uncertain significance ★★ ⚠ same condition
CNOT1 p.Arg369Cys Uncertain significance ★★ ⚠ same condition
CNOT1 p.Asn1162Thr Uncertain significance ★★ ⚠ same condition
CNOT1 p.Asn1295Ser Uncertain significance ★★ ⚠ same condition
CNOT1 p.Asn2199Lys Uncertain significance ★★ ⚠ same condition
CNOT1 p.Asn349Ser 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/cnot1-p-ile613thr (accessed [today's date]).

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