Is NOTCH2 p.Pro2168fs (c.6503del) pathogenic?

NOTCH2 p.Pro2168fs (c.6503del) is classified Pathogenic in NOTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-15). Absent from gnomAD; Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Pro2168fs (c.6503del)?

NOTCH2 p.Pro2168fs (c.6503del) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Pro2168fs (c.6503del) in the general population?

NOTCH2 p.Pro2168fs (c.6503del) is absent from gnomAD (gnomAD).

NOTCH2 p.Pro2168fs

c.6503del · rs1557802165 · VCV571329

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

Conditions

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	escapes	premature termination codon in the last exon (34 of 34) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -4.7

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.Pro2168fs
Coding: c.6503del
MANE Select: NM_024408
dbSNP: rs1557802165
Type: Deletion
Location: chr1:119916219 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 2168: a UniProt-annotated variant site (in hjcys); the 'disordered' region

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

Disease context

acroosteolysis dominant type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-pro2168fs (accessed [today's date]).

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