Is NOTCH2 p.Arg1069Gln (c.3206G>A) pathogenic?

NOTCH2 p.Arg1069Gln (c.3206G>A) is classified Conflicting classifications of pathogenicity in NOTCH2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.0726); Ultra-rare (popmax 0.04%, afr); Associated with Inborn genetic diseases.

What condition is associated with NOTCH2 p.Arg1069Gln (c.3206G>A)?

NOTCH2 p.Arg1069Gln (c.3206G>A) is associated with Inborn genetic diseases, acroosteolysis dominant type, Alagille syndrome due to a NOTCH2 point mutation (ClinVar).

How common is NOTCH2 p.Arg1069Gln (c.3206G>A) in the general population?

NOTCH2 p.Arg1069Gln (c.3206G>A) is ultra-rare (popmax 0.04%, afr) (gnomAD).

What do computational predictors say about NOTCH2 p.Arg1069Gln (c.3206G>A)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

NOTCH2 p.Arg1069Gln

c.3206G>A · rs146014987 · VCV134965

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -5.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.66
Regional constraint	o/e 0.77	unconstrained · MANE · 40 kb · p 1.4e-18 · regional, not allelic
Overall
CADD	10.76	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 0.04% African / African-American · 30/75,004 alleles

Filtering AF 0.0288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.00489% 79/1,614,104 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.04%	2,500
Admixed American	0.0167%	6,002
East Asian	0.00668%	14,961
Remaining individualsnot grpmax-eligible	0.0032%	31,253
European (non-Finnish)	0.0028%	35,758
South Asian	0.0011%	91,076

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.Arg1069Gln
Coding: c.3206G>A
MANE Select: NM_024408
dbSNP: rs146014987
Type: single nucleotide variant
Location: chr1:119937988 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 1069: a disulfide bond; the egf-like 28 domain

Full NOTCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acroosteolysis dominant type Alagille syndrome due to a NOTCH2 point mutation

Similar variants

NOTCH2 p.Arg1069Trp Uncertain significance ★ ⚠ same residue
NOTCH2 p.Arg1069= Likely benign ★ 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

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-arg1069gln (accessed [today's date]).

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