Is NOTCH1 p.Pro131= (c.393C>T) pathogenic?

NOTCH1 p.Pro131= (c.393C>T) is classified Likely benign in NOTCH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-14). Ultra-rare (popmax 0.0118%, amr); Associated with Adams-Oliver syndrome 5.

What condition is associated with NOTCH1 p.Pro131= (c.393C>T)?

NOTCH1 p.Pro131= (c.393C>T) is associated with Adams-Oliver syndrome 5, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is NOTCH1 p.Pro131= (c.393C>T) in the general population?

NOTCH1 p.Pro131= (c.393C>T) is ultra-rare (popmax 0.0118%, amr) (gnomAD).

NOTCH1 p.Pro131=

c.393C>T · rs1250243662 · VCV695421

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, 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 -15	GERP -3.8
Overall
CADD	2.584	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0118% Admixed American · 7/59,380 alleles

Filtering AF 0.00548% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00384%

Overall 0.00106% 17/1,606,970 alleles · ultra-rare exomes 14/1,454,770 · genomes 3/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0118%	8,483
East Asian	0.00671%	14,899
Remaining individualsnot grpmax-eligible	0.00161%	62,100
Finnishnot grpmax-eligible	0.00161%	62,194
European (non-Finnish)	0.000424%	235,662

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.Pro131=
Coding: c.393C>T
MANE Select: NM_017617
dbSNP: rs1250243662
Type: single nucleotide variant
Location: chr9:136523727 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 131: the egf-like 3 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

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-pro131 (accessed [today's date]).

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