Is NOTCH1 p.Pro284= (c.852G>A) pathogenic?

NOTCH1 p.Pro284= (c.852G>A) is classified Benign in NOTCH1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). Common (popmax 25.1%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Adams-Oliver syndrome 5.

What condition is associated with NOTCH1 p.Pro284= (c.852G>A)?

NOTCH1 p.Pro284= (c.852G>A) is associated with Adams-Oliver syndrome 5, familial thoracic aortic aneurysm and aortic dissection, aortic valve disease 1 (ClinVar).

NOTCH1 p.Pro284=

Q: How common is NOTCH1 p.Pro284= (c.852G>A) in the general population?

NOTCH1 p.Pro284= (c.852G>A) is common (popmax 25.1%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.852G>A · rs2229975 · VCV384692

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Common

common (popmax 25.1%, sas) — too common for a highly-penetrant pathogenic allele

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 -20	GERP -4.5
Overall
CADD	1.096	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 25.1% South Asian · 22,883/91,088 alleles

Filtering AF 24.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 24.7%

Overall 13.7% 221,140/1,612,772 alleles · common exomes 201,855/1,460,436 · genomes 19,285/152,336 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	25.1%	4
Ashkenazi Jewishnot grpmax-eligible	21.3%	5
Middle Eastern	16.9%	6
Amishnot grpmax-eligible	16.2%	6
Remaining individualsnot grpmax-eligible	13.8%	7
European (non-Finnish)	13.5%	7
African / African-American	10.7%	9
Finnishnot grpmax-eligible	10.1%	10
Admixed American	9.43%	11
East Asian	5.85%	17

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.Pro284=
Coding: c.852G>A
MANE Select: NM_017617
dbSNP: rs2229975
Type: single nucleotide variant
Location: chr9:136519456 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 284: the egf-like 7; calcium-binding domain

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 aortic valve disease 1

Similar variants

NOTCH1 p.Pro284Leu 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
NOTCH1 p.Cys1496Tyr 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-pro284 (accessed [today's date]).

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