Is NOTCH1 p.Pro2128= (c.6384G>C) pathogenic?

NOTCH1 p.Pro2128= (c.6384G>C) is classified Likely benign in NOTCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-27). Absent from gnomAD v4.1; Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with NOTCH1 p.Pro2128= (c.6384G>C)?

NOTCH1 p.Pro2128= (c.6384G>C) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is NOTCH1 p.Pro2128= (c.6384G>C) in the general population?

NOTCH1 p.Pro2128= (c.6384G>C) is absent from gnomAD v4.1 (gnomAD).

NOTCH1 p.Pro2128=

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.6384G>C · VCV3406883

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial thoracic aortic aneurysm and aortic dissection

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 -0.42	GERP -3.8
Overall
CADD	0.366	PHRED · no single calibrated threshold — expert panels disagree

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: NOTCH1
Protein: p.Pro2128=
Coding: c.6384G>C
MANE Select: NM_017617
Type: single nucleotide variant
Location: chr9:136497355 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB

Full NOTCH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

NOTCH1 p.Pro2128Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
NOTCH1 p.Pro2128Thr Uncertain significance ★ ⚠ same residue
NOTCH1 p.Pro2128Ala Likely benign ★ same residue
NOTCH1 c.1099+1G>T Pathogenic/Likely pathogenic ★★ same condition
NOTCH1 p.Arg448Ter Pathogenic ★★ same condition
NOTCH1 p.Cys1496Tyr Pathogenic/Likely pathogenic ★★ same condition
NOTCH1 c.1441+4C>T Uncertain significance ★★ same condition
NOTCH1 c.1904-3C>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/notch1-p-pro2128 (accessed [today's date]).

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