Is NOTCH1 p.Pro2349= (c.7047G>A) pathogenic?

NOTCH1 p.Pro2349= (c.7047G>A) is classified Benign/Likely benign in NOTCH1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-22). Ultra-rare (popmax 0.0156%, eas); Associated with aortic valve disease 1.

What condition is associated with NOTCH1 p.Pro2349= (c.7047G>A)?

NOTCH1 p.Pro2349= (c.7047G>A) is associated with aortic valve disease 1, Adams-Oliver syndrome 5, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is NOTCH1 p.Pro2349= (c.7047G>A) in the general population?

NOTCH1 p.Pro2349= (c.7047G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

NOTCH1 p.Pro2349=

c.7047G>A · rs775336930 · VCV390953

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Conditions

aortic valve disease 1

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 -12	GERP -3.9
Overall
CADD	0.188	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,896 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00564% 91/1,612,662 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,414
European (non-Finnish)	0.00653%	15,324
South Asian	0.00439%	22,769
Admixed American	0.00333%	30,002
Remaining individualsnot grpmax-eligible	0.0016%	62,454

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: NOTCH1
Protein: p.Pro2349=
Coding: c.7047G>A
MANE Select: NM_017617
dbSNP: rs775336930
Type: single nucleotide variant
Location: chr9:136496692 (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

aortic valve disease 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Adams-Oliver syndrome 5 familial thoracic aortic aneurysm and aortic dissection

Similar variants

NOTCH1 p.Pro2349Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
NOTCH1 p.Pro2349Ala Likely benign ★ same residue
NOTCH1 c.1099+1G>T Pathogenic/Likely pathogenic ★★ same condition
NOTCH1 c.3511-1G>A Likely pathogenic ★★ same condition
NOTCH1 p.Arg1107Ter Pathogenic ★★ same condition
NOTCH1 p.Arg448Ter Pathogenic ★★ same condition
NOTCH1 p.Arg56Ter Pathogenic ★★ same condition
NOTCH1 p.Asp1517Asn Pathogenic/Likely pathogenic ★★ 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-pro2349 (accessed [today's date]).

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