Is NOTCH2 p.Arg91= (c.273A>G) pathogenic?

NOTCH2 p.Arg91= (c.273A>G) is classified Conflicting classifications of pathogenicity in NOTCH2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-01). Ultra-rare (popmax 0.0165%, mid); Associated with Alagille syndrome due to a NOTCH2 point mutation.

How common is NOTCH2 p.Arg91= (c.273A>G) in the general population?

NOTCH2 p.Arg91= (c.273A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

NOTCH2 p.Arg91=

Q: What condition is associated with NOTCH2 p.Arg91= (c.273A>G)?

NOTCH2 p.Arg91= (c.273A>G) is associated with Alagille syndrome due to a NOTCH2 point mutation, acroosteolysis dominant type (ClinVar).

c.273A>G · rs201643251 · VCV3234143

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Alagille syndrome due to a NOTCH2 point mutation

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 -2.7
Overall
CADD	4.111	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.0047% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00431%

Overall 0.00533% 86/1,613,602 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
East Asian	0.00892%	11,212
European (non-Finnish)	0.00585%	17,099
South Asian	0.00549%	18,210
African / African-American	0.00401%	24,949
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Admixed American	0.00334%	29,979
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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.Arg91=
Coding: c.273A>G
MANE Select: NM_024408
dbSNP: rs201643251
Type: single nucleotide variant
Location: chr1:120005471 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 91: the egf-like 2 domain

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

Disease context

Alagille syndrome due to a NOTCH2 point mutation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acroosteolysis dominant type

Similar variants

NOTCH2 p.Arg91Leu Benign/Likely benign ★★ same residue
NOTCH2 p.Arg91Gln Uncertain significance ★ ⚠ same residue
NOTCH2 p.Arg91Ter Likely pathogenic ★ 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

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-arg91 (accessed [today's date]).

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