Is NOTCH1 p.Pro226= (c.678C>G) pathogenic?

NOTCH1 p.Pro226= (c.678C>G) is classified Likely benign in NOTCH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-19). Very rare (popmax 0.000874%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is NOTCH1 p.Pro226= (c.678C>G) in the general population?

NOTCH1 p.Pro226= (c.678C>G) is very rare (popmax 0.000874%, nfe) (gnomAD).

NOTCH1 p.Pro226=

Q: What condition is associated with NOTCH1 p.Pro226= (c.678C>G)?

NOTCH1 p.Pro226= (c.678C>G) is associated with familial thoracic aortic aneurysm and aortic dissection, Adams-Oliver syndrome 5 (ClinVar).

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.678C>G · rs950648628 · VCV1083413

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000874%, nfe)

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 0.18	GERP -1.6, phastCons 0.87
Overall
CADD	9.906	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000874% European (non-Finnish) · 10/1,143,768 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000322%

Overall 0.000647% 10/1,545,338 alleles · very rare exomes 9/1,393,096 · genomes 1/152,242 · joint denominator

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.Pro226=
Coding: c.678C>G
MANE Select: NM_017617
dbSNP: rs950648628
Type: single nucleotide variant
Location: chr9:136522914 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 226: the egf-like 6 domain

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

Also linked: Adams-Oliver syndrome 5

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

NOTCH1 p.Pro226Leu 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
NOTCH1 p.Asp1517Asn Pathogenic/Likely pathogenic ★★ same condition
NOTCH1 p.Cys1496Tyr 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-pro226 (accessed [today's date]).

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