Is NOTCH2 p.Asp875= (c.2625C>T) pathogenic?

NOTCH2 p.Asp875= (c.2625C>T) is classified Likely benign in NOTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). Ultra-rare (popmax 0.0164%, mid); Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Asp875= (c.2625C>T)?

NOTCH2 p.Asp875= (c.2625C>T) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Asp875= (c.2625C>T) in the general population?

NOTCH2 p.Asp875= (c.2625C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

NOTCH2 p.Asp875=

c.2625C>T · VCV3629144

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

acroosteolysis dominant type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.7
Overall
CADD	0.668	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000929% 15/1,614,040 alleles · ultra-rare exomes 12/1,461,884 · genomes 3/152,156 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
African / African-American	0.00534%	18,731
European (non-Finnish)	0.000847%	118,002

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.Asp875=
Coding: c.2625C>T
MANE Select: NM_024408
Type: single nucleotide variant
Location: chr1:119948541 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 875: the egf-like 23; 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.Asp875Glu 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-asp875 (accessed [today's date]).

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