Is NOTCH2 p.Cys433= (c.1299T>C) pathogenic?

NOTCH2 p.Cys433= (c.1299T>C) is classified Benign/Likely benign in NOTCH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.0467%, amr); Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Cys433= (c.1299T>C)?

NOTCH2 p.Cys433= (c.1299T>C) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Cys433= (c.1299T>C) in the general population?

NOTCH2 p.Cys433= (c.1299T>C) is ultra-rare (popmax 0.0467%, amr) (gnomAD).

NOTCH2 p.Cys433=

c.1299T>C · rs782774086 · VCV1169611

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, amr)

Conditions

acroosteolysis dominant type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.68	phastCons 0.94
Overall
CADD	8.953	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0467% Admixed American · 28/59,998 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0286%

Overall 0.00353% 57/1,614,000 alleles · ultra-rare exomes 53/1,461,788 · genomes 4/152,212 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0467%	2,143
European (non-Finnish)	0.00237%	42,142
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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: NOTCH2
Protein: p.Cys433=
Coding: c.1299T>C
MANE Select: NM_024408
dbSNP: rs782774086
Type: single nucleotide variant
Location: chr1:119967587 (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

Disease context

acroosteolysis dominant type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOTCH2 p.Cys433Tyr Uncertain significance ★ ⚠ same residue
NOTCH2 p.Cys433Phe Uncertain significance ★ ⚠ same residue
NOTCH2 p.Arg2003Ter Pathogenic/Likely pathogenic ★★ same condition
NOTCH2 p.Arg2400Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2223Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2263Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2285Ter Pathogenic/Likely pathogenic ★★ same condition
NOTCH2 c.2753-8T>A 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/notch2-p-cys433 (accessed [today's date]).

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