Is CNOT4 p.Val142Ala (c.425T>C) pathogenic?

CNOT4 p.Val142Ala (c.425T>C) is classified Uncertain significance in CNOT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely pathogenic (0.9975); Very rare (popmax 0.000171%, nfe).

How common is CNOT4 p.Val142Ala (c.425T>C) in the general population?

CNOT4 p.Val142Ala (c.425T>C) is very rare (popmax 0.000171%, nfe) (gnomAD).

What do computational predictors say about CNOT4 p.Val142Ala (c.425T>C)?

AlphaMissense predicts likely pathogenic (score 0.9975) — an in-silico prediction, not a clinical call.

CNOT4 p.Val142Ala

c.425T>C · VCV4004390

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9975 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9975	likely pathogenic
REVEL	0.473	indeterminate
SaProt	LLR -11.28	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.36	unconstrained · MANE · 24 kb · p 4.2e-20 · regional, not allelic
Overall
CADD	25.2	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 0.000171% European (non-Finnish) · 2/1,172,794 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000138% 2/1,453,508 alleles · very rare

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: CNOT4
Protein: p.Val142Ala
Coding: c.425T>C
MANE Select: NM_001190850
Type: single nucleotide variant
Location: chr7:135415210 (GRCh38)
Gene constraint: LOEUF 0.236 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.54 · 2 PDB
Residue 142: the rrm domain

Full CNOT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNOT4 p.Ala101Ser Uncertain significance ★ ⚠ same type
CNOT4 p.Ala459Thr Uncertain significance ★ ⚠ same type
CNOT4 p.Ala583Thr Uncertain significance ★ same type
CNOT4 p.Ala587Val Uncertain significance ★ same type
CNOT4 p.Ala649Pro Uncertain significance ★ same type
CNOT4 p.Ala669Thr Uncertain significance ★ same type
CNOT4 p.Arg323Gln Uncertain significance ★ ⚠ same type
CNOT4 p.Arg342His 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/cnot4-p-val142ala (accessed [today's date]).

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