Is NOTCH1 p.Pro593Arg (c.1778C>G) pathogenic?

NOTCH1 p.Pro593Arg (c.1778C>G) is classified Uncertain significance in NOTCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-28). AlphaMissense: likely benign (0.1049); Absent from gnomAD v4.1; Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with NOTCH1 p.Pro593Arg (c.1778C>G)?

NOTCH1 p.Pro593Arg (c.1778C>G) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is NOTCH1 p.Pro593Arg (c.1778C>G) in the general population?

NOTCH1 p.Pro593Arg (c.1778C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NOTCH1 p.Pro593Arg (c.1778C>G)?

AlphaMissense predicts likely benign (score 0.1049) — an in-silico prediction, not a clinical call.

NOTCH1 p.Pro593Arg

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.1778C>G · VCV4861110

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1049 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.1049	likely benign
REVEL	0.804	moderately pathogenic-leaning
SaProt	LLR -9.40	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 2,211 bp · p 2.3e-06 · regional, not allelic
Overall
CADD	28.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NOTCH1
Protein: p.Pro593Arg
Coding: c.1778C>G
MANE Select: NM_017617
Type: single nucleotide variant
Location: chr9:136515608 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 593: the egf-like 15; calcium-binding 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

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

NOTCH1 p.Pro593Leu Uncertain significance ★★ ⚠ 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
NOTCH1 c.4014+3A>G 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-pro593arg (accessed [today's date]).

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