Is NOTCH1 p.Arg1663Gln (c.4988G>A) pathogenic?

NOTCH1 p.Arg1663Gln (c.4988G>A) is classified Conflicting classifications of pathogenicity in NOTCH1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.12); Ultra-rare (popmax 0.0124%, afr); Associated with aortic valve disease 1.

What condition is associated with NOTCH1 p.Arg1663Gln (c.4988G>A)?

NOTCH1 p.Arg1663Gln (c.4988G>A) is associated with aortic valve disease 1, Adams-Oliver syndrome 5, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is NOTCH1 p.Arg1663Gln (c.4988G>A) in the general population?

NOTCH1 p.Arg1663Gln (c.4988G>A) is ultra-rare (popmax 0.0124%, afr) (gnomAD).

What do computational predictors say about NOTCH1 p.Arg1663Gln (c.4988G>A)?

AlphaMissense predicts likely benign (score 0.12) — an in-silico prediction, not a clinical call.

NOTCH1 p.Arg1663Gln

c.4988G>A · rs749490844 · VCV477936

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.12 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0124%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

aortic valve disease 1

Computational evidence

Protein change
AlphaMissense	0.12	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -9.97	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 7.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 12 kb · p 5.9e-08 · regional, not allelic
Overall
CADD	24.9	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 0.0124% African / African-American · 9/72,670 alleles

Filtering AF 0.00802% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00745%

Overall 0.0106% 162/1,534,572 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.083%	1,204
African / African-Americangrpmax	0.0124%	8,074
South Asian	0.0122%	8,223
Remaining individualsnot grpmax-eligible	0.0118%	8,464
East Asian	0.00982%	10,181
European (non-Finnish)	0.00948%	10,547
Admixed American	0.00199%	50,168

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1663Gln
Coding: c.4988G>A
MANE Select: NM_017617
dbSNP: rs749490844
Type: single nucleotide variant
Location: chr9:136504703 (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

aortic valve disease 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Adams-Oliver syndrome 5 familial thoracic aortic aneurysm and aortic dissection

Similar variants

NOTCH1 p.Arg1663Leu Uncertain significance ★ ⚠ same residue
NOTCH1 p.Arg1663Trp Conflicting classifications of pathogenicity ★ ⚠ 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-arg1663gln (accessed [today's date]).

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