Is NOTCH1 p.Ser784= (c.2352C>T) pathogenic?

NOTCH1 p.Ser784= (c.2352C>T) is classified Conflicting classifications of pathogenicity in NOTCH1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-12). Ultra-rare (popmax 0.0183%, amr); Associated with Adams-Oliver syndrome 5.

What condition is associated with NOTCH1 p.Ser784= (c.2352C>T)?

NOTCH1 p.Ser784= (c.2352C>T) is associated with Adams-Oliver syndrome 5, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is NOTCH1 p.Ser784= (c.2352C>T) in the general population?

NOTCH1 p.Ser784= (c.2352C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

NOTCH1 p.Ser784=

c.2352C>T · rs774701000 · VCV477897

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

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 -3.8	GERP -4.2
Overall
CADD	0.212	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/60,016 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00844%

Overall 0.00905% 146/1,612,788 alleles · ultra-rare exomes 130/1,460,440 · genomes 16/152,348 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,456
European (non-Finnish)	0.0106%	9,440
Remaining individualsnot grpmax-eligible	0.0064%	15,623
African / African-American	0.00533%	18,765
East Asian	0.00223%	44,886
South Asian	0.0011%	91,080

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.Ser784=
Coding: c.2352C>T
MANE Select: NM_017617
dbSNP: rs774701000
Type: single nucleotide variant
Location: chr9:136513393 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 784: 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 p.Ser784Thr Uncertain significance ★★ ⚠ same residue
NOTCH1 p.Ser784Gly 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-ser784 (accessed [today's date]).

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