Is NOTCH1 p.Pro935= (c.2805C>T) pathogenic?

NOTCH1 p.Pro935= (c.2805C>T) is classified Benign/Likely benign in NOTCH1 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-09). Ultra-rare (popmax 0.0236%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is NOTCH1 p.Pro935= (c.2805C>T) in the general population?

NOTCH1 p.Pro935= (c.2805C>T) is ultra-rare (popmax 0.0236%, nfe) (gnomAD).

NOTCH1 p.Pro935=

Q: What condition is associated with NOTCH1 p.Pro935= (c.2805C>T)?

NOTCH1 p.Pro935= (c.2805C>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.2805C>T · rs200332386 · VCV510414

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0236%, 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	<0.2	all four deltas below 0.2 · G>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP -15	GERP -4.5
Overall
CADD	0.436	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0236% European (non-Finnish) · 279/1,180,024 alleles

Filtering AF 0.0213% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.0187% 301/1,613,120 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0236%	4,229
Remaining individualsnot grpmax-eligible	0.0112%	8,924
South Asian	0.00768%	13,013
African / African-American	0.00534%	18,735
Admixed American	0.00333%	30,008
Finnishnot grpmax-eligible	0.00317%	31,540

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.Pro935=
Coding: c.2805C>T
MANE Select: NM_017617
dbSNP: rs200332386
Type: single nucleotide variant
Location: chr9:136509897 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 935: a disulfide bond; the egf-like 24 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 aortic valve disease 1

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

NOTCH1 p.Pro935Leu 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-pro935 (accessed [today's date]).

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