Is NOTCH2 p.Pro287Ala (c.859C>G) pathogenic?

NOTCH2 p.Pro287Ala (c.859C>G) is classified Uncertain significance in NOTCH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-23). AlphaMissense: likely benign (0.1192); Very rare (popmax 0.00161%, nfe); Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Pro287Ala (c.859C>G)?

NOTCH2 p.Pro287Ala (c.859C>G) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Pro287Ala (c.859C>G) in the general population?

NOTCH2 p.Pro287Ala (c.859C>G) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about NOTCH2 p.Pro287Ala (c.859C>G)?

AlphaMissense predicts likely benign (score 0.1192) — an in-silico prediction, not a clinical call.

NOTCH2 p.Pro287Ala

c.859C>G · rs372964061 · VCV2156020

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acroosteolysis dominant type

Computational evidence

Protein change
AlphaMissense	0.1192	likely benign
REVEL	0.702	pathogenic-leaning
SaProt	LLR -2.97	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 46 kb · p 1.7e-32 · regional, not allelic
Overall
CADD	24.6	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 0.00161% European (non-Finnish) · 19/1,179,608 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00118% 19/1,613,620 alleles · very rare exomes 17/1,461,318 · genomes 2/152,302 · 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.Pro287Ala
Coding: c.859C>G
MANE Select: NM_024408
dbSNP: rs372964061
Type: single nucleotide variant
Location: chr1:119986975 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 287: the egf-like 7; calcium-binding 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.Pro287Ser 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-pro287ala (accessed [today's date]).

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