Is NOTCH1 p.Pro2411= (c.7233A>G) pathogenic?

NOTCH1 p.Pro2411= (c.7233A>G) is classified Benign in NOTCH1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-02). Common (popmax 8.98%, afr) — too common for a highly-penetrant pathogenic allele; Associated with aortic valve disease 1.

What condition is associated with NOTCH1 p.Pro2411= (c.7233A>G)?

NOTCH1 p.Pro2411= (c.7233A>G) is associated with aortic valve disease 1, Adams-Oliver syndrome 5, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

NOTCH1 p.Pro2411=

Q: How common is NOTCH1 p.Pro2411= (c.7233A>G) in the general population?

NOTCH1 p.Pro2411= (c.7233A>G) is common (popmax 8.98%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.7233A>G · rs11574911 · VCV285559

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Common

common (popmax 8.98%, afr) — too common for a highly-penetrant pathogenic allele

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 -2.7	GERP -1.5
Overall
CADD	0.082	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.98% African / African-American · 6,742/75,038 alleles

Filtering AF 8.81% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.73%

Overall 0.556% 8,915/1,602,606 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.98%	11
Ashkenazi Jewishnot grpmax-eligible	1.26%	79
Admixed American	0.901%	111
Middle Eastern	0.844%	119
Remaining individualsnot grpmax-eligible	0.829%	121
European (non-Finnish)	0.0558%	1,793
South Asian	0.022%	4,554
Finnishnot grpmax-eligible	0.0208%	4,799
East Asian	0.00223%	44,874

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.Pro2411=
Coding: c.7233A>G
MANE Select: NM_017617
dbSNP: rs11574911
Type: single nucleotide variant
Location: chr9:136496506 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 2411: the 'disordered' region

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.Pro2411Ser Uncertain significance ★★ ⚠ same residue
NOTCH1 p.Pro2411Leu Uncertain significance ★ ⚠ same residue
NOTCH1 p.Pro2411Arg Uncertain significance ★ ⚠ 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

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-pro2411 (accessed [today's date]).

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