Is NOTCH1 p.Phe52= (c.156C>T) pathogenic?

NOTCH1 p.Phe52= (c.156C>T) is classified Benign/Likely benign in NOTCH1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-06-01). Rare (popmax 0.325%, sas); Associated with Adams-Oliver syndrome 5.

What condition is associated with NOTCH1 p.Phe52= (c.156C>T)?

NOTCH1 p.Phe52= (c.156C>T) is associated with Adams-Oliver syndrome 5, familial thoracic aortic aneurysm and aortic dissection, aortic valve disease 1 (ClinVar).

How common is NOTCH1 p.Phe52= (c.156C>T) in the general population?

NOTCH1 p.Phe52= (c.156C>T) is rare (popmax 0.325%, sas) (gnomAD).

NOTCH1 p.Phe52=

c.156C>T · rs536299678 · VCV415423

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.325%, sas)

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 -5.7	GERP -2.7
Overall
CADD	3.515	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.325% South Asian · 277/85,274 alleles

Filtering AF 0.293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.281%

Overall 0.0299% 465/1,556,182 alleles · rare exomes 434/1,403,880 · genomes 31/152,302 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.325%	308
Middle Eastern	0.202%	494
Remaining individualsnot grpmax-eligible	0.0547%	1,829
African / African-American	0.019%	5,266
European (non-Finnish)	0.0109%	9,208
Admixed American	0.00577%	17,327
East Asian	0.0024%	41,748

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.Phe52=
Coding: c.156C>T
MANE Select: NM_017617
dbSNP: rs536299678
Type: single nucleotide variant
Location: chr9:136523964 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 52: the egf-like 1 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.Phe52Ile 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-phe52 (accessed [today's date]).

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