Is CNOT1 p.Ala1368= (c.4104G>A) pathogenic?

CNOT1 p.Ala1368= (c.4104G>A) is classified Uncertain significance in CNOT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). Ultra-rare (popmax 0.0329%, mid); Associated with holoprosencephaly 12 with or without pancreatic agenesis.

What condition is associated with CNOT1 p.Ala1368= (c.4104G>A)?

CNOT1 p.Ala1368= (c.4104G>A) is associated with holoprosencephaly 12 with or without pancreatic agenesis (ClinVar).

How common is CNOT1 p.Ala1368= (c.4104G>A) in the general population?

CNOT1 p.Ala1368= (c.4104G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

CNOT1 p.Ala1368=

c.4104G>A · VCV3779106

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

holoprosencephaly 12 with or without pancreatic agenesis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.48	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -1.7	GERP -4.6
Overall
CADD	17.38	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,080 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00235% 38/1,613,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,040
South Asian	0.0307%	3,253
African / African-American	0.00667%	14,982
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	8.48e-05%	1,179,901

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.Ala1368=
Coding: c.4104G>A
MANE Select: NM_016284
Type: single nucleotide variant
Location: chr16:58545394 (GRCh38)
Gene constraint: LOEUF 0.064 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.22 · 21 PDB
Residue 1368: an α-helix; a UniProt-annotated variant site (in vibos); the 'interaction with cnot6, cnot6l, cnot7 and cnot8' region

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

Disease context

holoprosencephaly 12 with or without pancreatic agenesis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNOT1 p.Ala1368Val Uncertain significance ★★ ⚠ same residue
CNOT1 p.Arg535Cys Pathogenic ★★ same condition
CNOT1 p.Ile178Val Uncertain significance ★★ ⚠ same condition
CNOT1 p.Ser1466Ala Uncertain significance ★★ ⚠ same condition
CNOT1 c.4006+12A>G Benign ★★ same condition
CNOT1 c.5896-5C>T Benign ★★ same condition
CNOT1 p.Gln973= Benign ★★ same condition
CNOT1 p.Gly303= Benign ★★ 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-ala1368 (accessed [today's date]).

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