Is NOTCH1 p.Pro2238= (c.6714C>T) pathogenic?

NOTCH1 p.Pro2238= (c.6714C>T) is classified Benign/Likely benign in NOTCH1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-26). Rare (popmax 0.136%, eas); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is NOTCH1 p.Pro2238= (c.6714C>T) in the general population?

NOTCH1 p.Pro2238= (c.6714C>T) is rare (popmax 0.136%, eas) (gnomAD).

NOTCH1 p.Pro2238=

Q: What condition is associated with NOTCH1 p.Pro2238= (c.6714C>T)?

NOTCH1 p.Pro2238= (c.6714C>T) is associated with familial thoracic aortic aneurysm and aortic dissection, Adams-Oliver syndrome 5, aortic valve disease 1 (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.6714C>T · rs201499253 · VCV477964

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.136%, eas)

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 -3.8	GERP -4.2
Overall
CADD	0.288	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.136% East Asian · 61/44,814 alleles

Filtering AF 0.109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0988%

Overall 0.00652% 105/1,609,436 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.136%	735
Admixed American	0.00834%	11,984
Remaining individualsnot grpmax-eligible	0.00641%	15,590
South Asian	0.0044%	22,746
African / African-American	0.00267%	37,486
European (non-Finnish)	0.00246%	40,630

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.Pro2238=
Coding: c.6714C>T
MANE Select: NM_017617
dbSNP: rs201499253
Type: single nucleotide variant
Location: chr9:136497025 (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

Also linked: Adams-Oliver syndrome 5 aortic valve disease 1

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

NOTCH1 p.Pro2238Ser 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-pro2238 (accessed [today's date]).

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