Is NOTCH2 p.Asp262= (c.786T>C) pathogenic?

NOTCH2 p.Asp262= (c.786T>C) is classified Conflicting classifications of pathogenicity in NOTCH2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-04). Ultra-rare (popmax 0.0201%, eas); Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Asp262= (c.786T>C)?

NOTCH2 p.Asp262= (c.786T>C) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Asp262= (c.786T>C) in the general population?

NOTCH2 p.Asp262= (c.786T>C) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

NOTCH2 p.Asp262=

c.786T>C · rs374224226 · VCV596064

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

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 -0.63
Overall
CADD	5.938	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0201% East Asian · 9/44,868 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.0111% 179/1,613,734 alleles · ultra-rare exomes 156/1,461,416 · genomes 23/152,318 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0352%	2,840
East Asiangrpmax	0.0201%	4,985
South Asian	0.0165%	6,071
African / African-American	0.0133%	7,503
European (non-Finnish)	0.01%	9,997
Admixed American	0.005%	19,997
Finnishnot grpmax-eligible	0.00312%	32,018

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp262=
Coding: c.786T>C
MANE Select: NM_024408
dbSNP: rs374224226
Type: single nucleotide variant
Location: chr1:119987048 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 262: 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.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-asp262 (accessed [today's date]).

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