Is CNOT1 p.Ile178Val (c.532A>G) pathogenic?

CNOT1 p.Ile178Val (c.532A>G) is classified Uncertain significance in CNOT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-22). AlphaMissense: likely benign (0.0942); Ultra-rare (popmax 0.0259%, nfe); Associated with holoprosencephaly 12 with or without pancreatic agenesis.

What condition is associated with CNOT1 p.Ile178Val (c.532A>G)?

CNOT1 p.Ile178Val (c.532A>G) is associated with holoprosencephaly 12 with or without pancreatic agenesis (ClinVar).

How common is CNOT1 p.Ile178Val (c.532A>G) in the general population?

CNOT1 p.Ile178Val (c.532A>G) is ultra-rare (popmax 0.0259%, nfe) (gnomAD).

What do computational predictors say about CNOT1 p.Ile178Val (c.532A>G)?

AlphaMissense predicts likely benign (score 0.0942) — an in-silico prediction, not a clinical call.

CNOT1 p.Ile178Val

c.532A>G · VCV3671161

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0942 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0259%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

holoprosencephaly 12 with or without pancreatic agenesis

Computational evidence

Protein change
AlphaMissense	0.0942	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -3.62	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 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 43 kb · p 6e-23 · 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 0.0259% European (non-Finnish) · 306/1,179,878 alleles

Filtering AF 0.0235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0226%

Overall 0.0195% 314/1,613,100 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0259%	3,856
African / African-American	0.00535%	18,697
Remaining individualsnot grpmax-eligible	0.0048%	20,818
Admixed American	0.00167%	59,946

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.Ile178Val
Coding: c.532A>G
MANE Select: NM_016284
Type: single nucleotide variant
Location: chr16:58586650 (GRCh38)
Gene constraint: LOEUF 0.064 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.22 · 21 PDB
Residue 178: a UniProt-annotated variant site (in vibos); an α-helix

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.Arg535Cys Pathogenic ★★ 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
CNOT1 p.Leu1376= Benign ★★ same condition
CNOT1 p.Tyr1572= 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-ile178val (accessed [today's date]).

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