NOTCH2 p.Phe646fs
c.1938del · VCV3673622
Pathogenic
Single submitter
Classification
Pathogenic
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
Consequence
frameshift
predicted LoF
gnomAD v4.1
Rare
Conditions
1
acroosteolysis dominant type
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 12 of 34 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 7.6 | phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Variant & gene context
- Gene
- NOTCH2
- Protein
- p.Phe646fs
- Coding
- c.1938del
- MANE Select
- NM_024408
- Type
- Deletion
- Location
- chr1:119959480 (GRCh38)
- Gene constraint
- LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 59.51 · 2 PDB
- Residue 646
- the egf-like 17; calcium-binding domain
Similar variants
- NOTCH2 p.Glu952fs Likely pathogenic ★★ same condition
- NOTCH2 p.Leu1995fs Pathogenic ★★ same condition
- NOTCH2 p.Val2151fs Likely pathogenic ★★ same condition
- NOTCH2 c.3523-15_3523-13del Likely benign ★★ same condition
- NOTCH2 p.Ala1700fs Likely pathogenic ★ same condition
- NOTCH2 p.Ala2214fs Likely pathogenic ★ same condition
- NOTCH2 p.Arg2047fs Likely pathogenic ★ same condition
- NOTCH2 p.Asp1782fs 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/notch2-p-phe646fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown