Is NOTCH1 p.Ser652= (c.1956G>A) pathogenic?

NOTCH1 p.Ser652= (c.1956G>A) is classified Likely benign in NOTCH1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-23). Ultra-rare (popmax 0.0574%, afr); Associated with aortic valve disease 1.

What condition is associated with NOTCH1 p.Ser652= (c.1956G>A)?

NOTCH1 p.Ser652= (c.1956G>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.Ser652= (c.1956G>A) in the general population?

NOTCH1 p.Ser652= (c.1956G>A) is ultra-rare (popmax 0.0574%, afr) (gnomAD).

NOTCH1 p.Ser652=

c.1956G>A · rs376101458 · VCV477885

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0574%, afr)

Conditions

aortic valve disease 1

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 -16	GERP -4.5
Overall
CADD	1.764	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0574% African / African-American · 43/74,926 alleles

Filtering AF 0.0437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.039%

Overall 0.00428% 69/1,612,950 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0574%	1,742
Remaining individualsnot grpmax-eligible	0.008%	12,494
Admixed American	0.00333%	30,000
Finnishnot grpmax-eligible	0.00159%	62,962
European (non-Finnish)	0.00144%	69,412
South Asian	0.0011%	91,094

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.Ser652=
Coding: c.1956G>A
MANE Select: NM_017617
dbSNP: rs376101458
Type: single nucleotide variant
Location: chr9:136515348 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 652: a disulfide bond; the egf-like 17; calcium-binding domain

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.Ser652Leu 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
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-ser652 (accessed [today's date]).

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