Is NOTCH1 p.Gly1526Val (c.4577G>T) pathogenic?

NOTCH1 p.Gly1526Val (c.4577G>T) is classified Uncertain significance in NOTCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-19). AlphaMissense: likely benign (0.1019); Very rare (popmax 0.00187%, amr); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with NOTCH1 p.Gly1526Val (c.4577G>T)?

NOTCH1 p.Gly1526Val (c.4577G>T) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is NOTCH1 p.Gly1526Val (c.4577G>T) in the general population?

NOTCH1 p.Gly1526Val (c.4577G>T) is very rare (popmax 0.00187%, amr) (gnomAD).

What do computational predictors say about NOTCH1 p.Gly1526Val (c.4577G>T)?

AlphaMissense predicts likely benign (score 0.1019) — an in-silico prediction, not a clinical call.

NOTCH1 p.Gly1526Val

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.4577G>T · VCV3880482

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1019 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00187%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.1019	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -6.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.85	GERP -2.2, phastCons 0.17
Regional constraint	o/e 0.86	unconstrained · MANE · 12 kb · p 5.9e-08 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00187% Admixed American · 1/53,548 alleles

Overall 0.00019% 3/1,576,066 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00187%	53,548
Finnishnot grpmax-eligible	0.00167%	60,060
European (non-Finnish)	8.61e-05%	1,161,303

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.Gly1526Val
Coding: c.4577G>T
MANE Select: NM_017617
Type: single nucleotide variant
Location: chr9:136505319 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB

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.Gly1526Cys Uncertain significance ★ same residue
NOTCH1 p.Gly1526Ala 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

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-gly1526val (accessed [today's date]).

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