Is NOTCH2 p.Pro1309= (c.3927C>G) pathogenic?

NOTCH2 p.Pro1309= (c.3927C>G) is classified Likely benign in NOTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-18). Very rare (popmax 0.000255%, nfe); Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Pro1309= (c.3927C>G)?

NOTCH2 p.Pro1309= (c.3927C>G) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Pro1309= (c.3927C>G) in the general population?

NOTCH2 p.Pro1309= (c.3927C>G) is very rare (popmax 0.000255%, nfe) (gnomAD).

NOTCH2 p.Pro1309=

c.3927C>G · VCV3675810

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Conditions

acroosteolysis dominant type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.24	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.78	phastCons 1
Overall
CADD	14.51	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000255% European (non-Finnish) · 3/1,177,650 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,609,430 alleles · very rare exomes 1/1,457,362 · genomes 2/152,068 · joint denominator

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.Pro1309=
Coding: c.3927C>G
MANE Select: NM_024408
Type: single nucleotide variant
Location: chr1:119926577 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 1309: the egf-like 34 domain

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.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
NOTCH2 c.874+4T>C 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-pro1309 (accessed [today's date]).

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