Is NOTCH1 p.Pro422= (c.1266C>G) pathogenic?

NOTCH1 p.Pro422= (c.1266C>G) is classified Benign/Likely benign in NOTCH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-22). Very rare (popmax 0.000424%, nfe); Associated with Adams-Oliver syndrome 5.

What condition is associated with NOTCH1 p.Pro422= (c.1266C>G)?

NOTCH1 p.Pro422= (c.1266C>G) is associated with Adams-Oliver syndrome 5, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is NOTCH1 p.Pro422= (c.1266C>G) in the general population?

NOTCH1 p.Pro422= (c.1266C>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

NOTCH1 p.Pro422=

c.1266C>G · rs762533002 · VCV1007757

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

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 0.17	GERP -4.5, phastCons 0.79
Overall
CADD	8.043	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,900 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000621% 10/1,610,798 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00655%	15,259
Remaining individualsnot grpmax-eligible	0.0016%	62,448
European (non-Finnish)grpmax	0.000424%	235,980

Finnish 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.Pro422=
Coding: c.1266C>G
MANE Select: NM_017617
dbSNP: rs762533002
Type: single nucleotide variant
Location: chr9:136517927 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 422: a disulfide bond; the egf-like 11; calcium-binding 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-pro422 (accessed [today's date]).

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