Is NOTCH2 p.Asp341fs (c.1021dup) pathogenic?

NOTCH2 p.Asp341fs (c.1021dup) is classified Pathogenic in NOTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-11-28). Absent from gnomAD.

How common is NOTCH2 p.Asp341fs (c.1021dup) in the general population?

NOTCH2 p.Asp341fs (c.1021dup) is absent from gnomAD (gnomAD).

NOTCH2 p.Asp341fs

c.1021dup · rs1553200134 · VCV498834

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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 6 of 34
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: NOTCH2
Protein: p.Asp341fs
Coding: c.1021dup
MANE Select: NM_024408
dbSNP: rs1553200134
Type: Duplication
Location: chr1:119969597 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 341: the egf-like 9; calcium-binding domain

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

Similar variants

NOTCH2 p.Asp341= Likely benign ★ same residue
NOTCH2 p.Arg1889fs Pathogenic ★★ same type
NOTCH2 p.Ile2304fs Pathogenic/Likely pathogenic ★★ same type
NOTCH2 p.Ala1083fs Pathogenic ★ same type
NOTCH2 p.Ala2356fs Likely pathogenic ★ same type
NOTCH2 p.Asn2066fs Likely pathogenic ★ same type
NOTCH2 p.Cys302fs Likely pathogenic ★ same type
NOTCH2 p.His885fs 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-asp341fs (accessed [today's date]).

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