Is NOTCH2 p.Phe2268Ile (c.6802T>A) pathogenic?

NOTCH2 p.Phe2268Ile (c.6802T>A) is classified Uncertain significance in NOTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-16). AlphaMissense: ambiguous (0.3572); Very rare (popmax 8.47e-05%, nfe); Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Phe2268Ile (c.6802T>A)?

NOTCH2 p.Phe2268Ile (c.6802T>A) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Phe2268Ile (c.6802T>A) in the general population?

NOTCH2 p.Phe2268Ile (c.6802T>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about NOTCH2 p.Phe2268Ile (c.6802T>A)?

AlphaMissense predicts ambiguous (score 0.3572) — an in-silico prediction, not a clinical call.

NOTCH2 p.Phe2268Ile

c.6802T>A · rs149580724 · VCV1473714

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3572 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

acroosteolysis dominant type

Computational evidence

Protein change
AlphaMissense	0.3572	ambiguous
REVEL	0.378	indeterminate
SaProt	LLR -5.77	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,256 bp · p 0.14 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.84e-05% 1/1,461,874 alleles · very rare

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.Phe2268Ile
Coding: c.6802T>A
MANE Select: NM_024408
dbSNP: rs149580724
Type: single nucleotide variant
Location: chr1:119915920 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 2268: a UniProt-annotated variant site (in hjcys)

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.Phe2268Leu Uncertain significance ★★ ⚠ same residue
NOTCH2 p.Arg2003Ter Pathogenic/Likely pathogenic ★★ same condition
NOTCH2 p.Arg2400Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2223Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2263Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2285Ter Pathogenic/Likely pathogenic ★★ same condition
NOTCH2 c.2753-8T>A Uncertain significance ★★ same condition
NOTCH2 c.5214-10A>G Uncertain significance ★★ 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-phe2268ile (accessed [today's date]).

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