Is NOTCH1 p.Arg1663Trp (c.4987C>T) pathogenic?

NOTCH1 p.Arg1663Trp (c.4987C>T) is classified Conflicting classifications of pathogenicity in NOTCH1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-25). AlphaMissense: likely benign (0.1647); Very rare (popmax 0.00246%, eas); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with NOTCH1 p.Arg1663Trp (c.4987C>T)?

NOTCH1 p.Arg1663Trp (c.4987C>T) is associated with familial thoracic aortic aneurysm and aortic dissection, Adams-Oliver syndrome 5 (ClinVar).

How common is NOTCH1 p.Arg1663Trp (c.4987C>T) in the general population?

NOTCH1 p.Arg1663Trp (c.4987C>T) is very rare (popmax 0.00246%, eas) (gnomAD).

What do computational predictors say about NOTCH1 p.Arg1663Trp (c.4987C>T)?

AlphaMissense predicts likely benign (score 0.1647) — an in-silico prediction, not a clinical call.

NOTCH1 p.Arg1663Trp

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.4987C>T · rs769050541 · VCV1744553

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.1647	likely benign
REVEL	0.497	indeterminate
SaProt	LLR -11.75	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.29	donor gain · deltas
Pangolin	Δ0.22	gain · loss 0.13 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 12 kb · p 5.9e-08 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.00246% East Asian · 1/40,718 alleles

Filtering AF 0.00115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000932%

Overall 0.0015% 23/1,535,020 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00246%	40,718
European (non-Finnish)	0.00176%	56,965
African / African-American	0.00138%	72,648
South Asian	0.00121%	82,436

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.Arg1663Trp
Coding: c.4987C>T
MANE Select: NM_017617
dbSNP: rs769050541
Type: single nucleotide variant
Location: chr9:136504704 (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

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 p.Arg1663Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
NOTCH1 p.Arg1663Leu Uncertain significance ★ ⚠ same residue
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

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-arg1663trp (accessed [today's date]).

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