Is NOTCH2 p.Pro6fs (c.17_18del) pathogenic?

NOTCH2 p.Pro6fs (c.1718del) is classified Benign/Likely benign in NOTCH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-05-22). Very rare (popmax 0.000518%, nfe).

How common is NOTCH2 p.Pro6fs (c.17_18del) in the general population?

NOTCH2 p.Pro6fs (c.17_18del) is very rare (popmax 0.000518%, nfe) (gnomAD).

NOTCH2 p.Pro6fs

c.17_18del · rs372504208 · VCV218795

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000518%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 1 of 34
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.8	phastCons 1
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000518% European (non-Finnish) · 6/1,159,358 alleles

Filtering AF 0.000186% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000122%

Overall 0.00045% 7/1,556,202 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00165%	60,516
European (non-Finnish)grpmax	0.000518%	193,226

Remaining individuals 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: NOTCH2
Protein: p.Pro6fs
Coding: c.17_18del
MANE Select: NM_024408
dbSNP: rs372504208
Type: Deletion
Location: chr1:120069389 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB

Full NOTCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NOTCH2 p.Pro6Ser Uncertain significance ★ ⚠ same residue
NOTCH2 p.Pro6= Likely benign ★ same residue
NOTCH2 p.Glu1586fs Likely pathogenic ★★ same type
NOTCH2 p.Glu952fs Likely pathogenic ★★ same type
NOTCH2 p.Leu1995fs Pathogenic ★★ same type
NOTCH2 p.Val2151fs Likely pathogenic ★★ same type
NOTCH2 c.3523-15_3523-13del Likely benign ★★ same type
NOTCH2 p.Ala1700fs Likely pathogenic ★ same type

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/notch2-p-pro6fs (accessed [today's date]).

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