Is NOTCH2 p.Cys433Phe (c.1298G>T) pathogenic?

NOTCH2 p.Cys433Phe (c.1298G>T) is classified Uncertain significance in NOTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-04). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1.

How common is NOTCH2 p.Cys433Phe (c.1298G>T) in the general population?

NOTCH2 p.Cys433Phe (c.1298G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NOTCH2 p.Cys433Phe (c.1298G>T)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

NOTCH2 p.Cys433Phe

c.1298G>T · VCV4908430

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 1% in NOTCH2
REVEL	0.971	strongly pathogenic-leaning
SaProt	LLR -14.44	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 46 kb · p 1.7e-32 · regional, not allelic
Overall
CADD	29.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NOTCH2
Protein: p.Cys433Phe
Coding: c.1298G>T
MANE Select: NM_024408
Type: single nucleotide variant
Location: chr1:119967588 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 433: a disulfide bond; the egf-like 11; calcium-binding domain; a β-strand

Full NOTCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NOTCH2 p.Cys433= Benign/Likely benign ★★ same residue
NOTCH2 p.Cys433Tyr Uncertain significance ★ ⚠ same residue
NOTCH2 p.Arg2003Ter Pathogenic/Likely pathogenic ★★ same type
NOTCH2 p.Arg2400Ter Pathogenic ★★ same type
NOTCH2 p.Gln2223Ter Pathogenic ★★ same type
NOTCH2 p.Gln2263Ter Pathogenic ★★ same type
NOTCH2 p.Gln2285Ter Pathogenic/Likely pathogenic ★★ same type
NOTCH2 c.2753-8T>A 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/notch2-p-cys433phe (accessed [today's date]).

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