Is NOTCH1 p.Ser417Pro (c.1249T>C) pathogenic?

NOTCH1 p.Ser417Pro (c.1249T>C) is classified Uncertain significance in NOTCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: likely pathogenic (0.7455); Very rare (popmax 8.56e-05%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with NOTCH1 p.Ser417Pro (c.1249T>C)?

NOTCH1 p.Ser417Pro (c.1249T>C) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is NOTCH1 p.Ser417Pro (c.1249T>C) in the general population?

NOTCH1 p.Ser417Pro (c.1249T>C) is very rare (popmax 8.56e-05%, nfe) (gnomAD).

What do computational predictors say about NOTCH1 p.Ser417Pro (c.1249T>C)?

AlphaMissense predicts likely pathogenic (score 0.7455) — an in-silico prediction, not a clinical call.

NOTCH1 p.Ser417Pro

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.1249T>C · VCV3406831

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7455 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.56e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.7455	likely pathogenic
REVEL	0.605	indeterminate
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.35	GERP -3.6, phastCons 0.002
Regional constraint	o/e 0.49	unconstrained · MANE · 867 bp · p 4.9e-12 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.56e-05% European (non-Finnish) · 1/1,168,254 alleles

Overall 6.3e-05% 1/1,588,522 alleles · very rare exomes 1/1,436,562 · genomes 0/151,960 · 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.Ser417Pro
Coding: c.1249T>C
MANE Select: NM_017617
Type: single nucleotide variant
Location: chr9:136518143 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 417: the egf-like 11; calcium-binding domain; an α-helix

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

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

NOTCH1 p.Ser417= Likely benign ★★ same residue
NOTCH1 p.Ser417Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
NOTCH1 c.1099+1G>T Pathogenic/Likely pathogenic ★★ same condition
NOTCH1 p.Arg448Ter Pathogenic ★★ same condition
NOTCH1 p.Cys1496Tyr Pathogenic/Likely pathogenic ★★ same condition
NOTCH1 c.1441+4C>T Uncertain significance ★★ same condition
NOTCH1 c.1904-3C>A Uncertain significance ★★ same condition
NOTCH1 c.1904-3C>T Uncertain significance ★★ 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-ser417pro (accessed [today's date]).

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