Is NOTCH1 p.Ser201Phe (c.602C>T) pathogenic?

NOTCH1 p.Ser201Phe (c.602C>T) is classified Uncertain significance in NOTCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-08). AlphaMissense: ambiguous (0.4034); Very rare (popmax 8.67e-05%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with NOTCH1 p.Ser201Phe (c.602C>T)?

NOTCH1 p.Ser201Phe (c.602C>T) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is NOTCH1 p.Ser201Phe (c.602C>T) in the general population?

NOTCH1 p.Ser201Phe (c.602C>T) is very rare (popmax 8.67e-05%, nfe) (gnomAD).

What do computational predictors say about NOTCH1 p.Ser201Phe (c.602C>T)?

AlphaMissense predicts ambiguous (score 0.4034) — an in-silico prediction, not a clinical call.

NOTCH1 p.Ser201Phe

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.602C>T · rs2540468232 · VCV2586761

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4034 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.67e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.4034	ambiguous
REVEL	0.761	pathogenic-leaning
SaProt	LLR -10.40	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 27 kb · p 4.1e-08 · regional, not allelic
Overall
CADD	27.5	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 8.67e-05% European (non-Finnish) · 1/1,152,860 alleles

Overall 6.41e-05% 1/1,560,184 alleles · very rare exomes 1/1,407,828 · genomes 0/152,356 · 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.Ser201Phe
Coding: c.602C>T
MANE Select: NM_017617
dbSNP: rs2540468232
Type: single nucleotide variant
Location: chr9:136522990 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 201: the egf-like 5; calcium-binding domain; a β-strand

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 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
NOTCH1 c.4014+3A>G Uncertain significance ★★ same condition
NOTCH1 c.5019-3C>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-ser201phe (accessed [today's date]).

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