Is NOTCH1 p.Phe783= (c.2349C>T) pathogenic?

NOTCH1 p.Phe783= (c.2349C>T) is classified Benign/Likely benign in NOTCH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-10). Ultra-rare (popmax 0.0746%, afr); Associated with Adams-Oliver syndrome 5.

What condition is associated with NOTCH1 p.Phe783= (c.2349C>T)?

NOTCH1 p.Phe783= (c.2349C>T) is associated with Adams-Oliver syndrome 5, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is NOTCH1 p.Phe783= (c.2349C>T) in the general population?

NOTCH1 p.Phe783= (c.2349C>T) is ultra-rare (popmax 0.0746%, afr) (gnomAD).

NOTCH1 p.Phe783=

c.2349C>T · rs200092299 · VCV698886

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0746%, afr)

Conditions

Adams-Oliver syndrome 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP -0.28, phastCons 1
Overall
CADD	11.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0746% African / African-American · 56/75,064 alleles

Filtering AF 0.0589% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0533%

Overall 0.00391% 63/1,612,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0746%	1,340
Admixed American	0.00666%	15,008
Remaining individualsnot grpmax-eligible	0.0032%	31,248
European (non-Finnish)	8.47e-05%	1,180,020

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.Phe783=
Coding: c.2349C>T
MANE Select: NM_017617
dbSNP: rs200092299
Type: single nucleotide variant
Location: chr9:136513396 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 783: a disulfide bond; the egf-like 20 domain; a β-strand

Full NOTCH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Adams-Oliver syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

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
NOTCH1 p.Cys1496Tyr Pathogenic/Likely pathogenic ★★ same condition
NOTCH1 p.Gln1466Ter 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-phe783 (accessed [today's date]).

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