Is NOTCH2 p.Arg1048= (c.3144C>T) pathogenic?

NOTCH2 p.Arg1048= (c.3144C>T) is classified Likely benign in NOTCH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-28). Ultra-rare (popmax 0.0166%, mid); Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Arg1048= (c.3144C>T)?

NOTCH2 p.Arg1048= (c.3144C>T) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Arg1048= (c.3144C>T) in the general population?

NOTCH2 p.Arg1048= (c.3144C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

NOTCH2 p.Arg1048=

c.3144C>T · rs782309717 · VCV1905704

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

acroosteolysis dominant type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	phastCons 1
Overall
CADD	8.362	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,042 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000558% 9/1,613,998 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,042
Remaining individualsnot grpmax-eligible	0.0048%	20,824
European (non-Finnish)	0.000424%	236,005

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.Arg1048=
Coding: c.3144C>T
MANE Select: NM_024408
dbSNP: rs782309717
Type: single nucleotide variant
Location: chr1:119940594 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 1048: a disulfide bond; the egf-like 27; 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.Arg1048His 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-arg1048 (accessed [today's date]).

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