Is NOTCH1 p.Phe1749= (c.5247C>T) pathogenic?

NOTCH1 p.Phe1749= (c.5247C>T) is classified Likely benign in NOTCH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-21). Very rare (popmax 0.00669%, eas); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with NOTCH1 p.Phe1749= (c.5247C>T)?

NOTCH1 p.Phe1749= (c.5247C>T) is associated with familial thoracic aortic aneurysm and aortic dissection, Adams-Oliver syndrome 5 (ClinVar).

How common is NOTCH1 p.Phe1749= (c.5247C>T) in the general population?

NOTCH1 p.Phe1749= (c.5247C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

NOTCH1 p.Phe1749=

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.5247C>T · rs762483384 · VCV699395

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00669%, 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	<0.2	all four deltas below 0.2 · G>T here scores Δ0.73 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.47	GERP -2.1, phastCons 0.11
Overall
CADD	10.88	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% East Asian · 3/44,850 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.00118% 19/1,611,296 alleles · very rare exomes 17/1,459,126 · genomes 2/152,170 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,950
South Asian	0.0033%	30,347
Remaining individualsnot grpmax-eligible	0.00321%	31,171
European (non-Finnish)	0.000933%	107,226

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.Phe1749=
Coding: c.5247C>T
MANE Select: NM_017617
dbSNP: rs762483384
Type: single nucleotide variant
Location: chr9:136502409 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 1749: a turn; the 'interaction with psen1' region

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 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
NOTCH1 p.Gln1466Ter 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-phe1749 (accessed [today's date]).

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