Is NOTCH2 p.Arg5= (c.15C>T) pathogenic?

NOTCH2 p.Arg5= (c.15C>T) is classified Benign in NOTCH2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-11-26). Common (popmax 18.6%, sas) — too common for a highly-penetrant pathogenic allele; Associated with Alagille syndrome due to a NOTCH2 point mutation.

NOTCH2 p.Arg5=

Q: What condition is associated with NOTCH2 p.Arg5= (c.15C>T)?

NOTCH2 p.Arg5= (c.15C>T) is associated with Alagille syndrome due to a NOTCH2 point mutation, acroosteolysis dominant type (ClinVar).

Q: How common is NOTCH2 p.Arg5= (c.15C>T) in the general population?

NOTCH2 p.Arg5= (c.15C>T) is common (popmax 18.6%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.15C>T · rs4021006 · VCV1174922

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 18.6%, sas) — too common for a highly-penetrant pathogenic allele

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 2.9	phastCons 1
Overall
CADD	12.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 18.6% South Asian · 14,984/80,442 alleles

Filtering AF 18.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.3%

Overall 12.2% 188,460/1,543,762 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	18.6%	5
European (non-Finnish)	12.4%	8
Remaining individualsnot grpmax-eligible	12%	8
Finnishnot grpmax-eligible	11.4%	9
African / African-American	11%	9
Admixed American	10.6%	9
Middle Eastern	10%	10
Ashkenazi Jewishnot grpmax-eligible	7.63%	13
Amishnot grpmax-eligible	7.36%	14
East Asian	4.68%	21

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.Arg5=
Coding: c.15C>T
MANE Select: NM_024408
dbSNP: rs4021006
Type: single nucleotide variant
Location: chr1:120069392 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB

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.Arg5Leu 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
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-arg5 (accessed [today's date]).

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