Is NOTCH2 p.Val2380= (c.7140G>C) pathogenic?

NOTCH2 p.Val2380= (c.7140G>C) is classified Likely benign in NOTCH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). Rare (popmax 0.163%, amr); Associated with Alagille syndrome due to a NOTCH2 point mutation.

What condition is associated with NOTCH2 p.Val2380= (c.7140G>C)?

NOTCH2 p.Val2380= (c.7140G>C) is associated with Alagille syndrome due to a NOTCH2 point mutation, acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Val2380= (c.7140G>C) in the general population?

NOTCH2 p.Val2380= (c.7140G>C) is rare (popmax 0.163%, amr) (gnomAD).

NOTCH2 p.Val2380=

c.7140G>C · rs150785478 · VCV1574670

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.163%, amr)

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 3.3	phastCons 1
Overall
CADD	7.585	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.163% Admixed American · 98/60,016 alleles

Filtering AF 0.137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.127%

Overall 0.00756% 122/1,614,010 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.163%	612
Remaining individualsnot grpmax-eligible	0.0352%	2,841
African / African-American	0.00266%	37,526

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.Val2380=
Coding: c.7140G>C
MANE Select: NM_024408
dbSNP: rs150785478
Type: single nucleotide variant
Location: chr1:119915582 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 2380: a UniProt-annotated variant site (in hjcys); a UniProt-annotated variant site (in hjcys; loss of interaction with fbw7; decreased ubiquitination); the 'disordered' region

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.Val2380Met Uncertain significance ★ ⚠ same residue
NOTCH2 p.Val2380fs 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

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-val2380 (accessed [today's date]).

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