Is NOTCH2 p.Ser2379Phe (c.7136C>T) pathogenic?

NOTCH2 p.Ser2379Phe (c.7136C>T) is classified Conflicting classifications of pathogenicity in NOTCH2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-17). AlphaMissense: ambiguous (0.3892); Ultra-rare (popmax 0.0171%, nfe); Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Ser2379Phe (c.7136C>T)?

NOTCH2 p.Ser2379Phe (c.7136C>T) is associated with acroosteolysis dominant type, Alagille syndrome due to a NOTCH2 point mutation (ClinVar).

How common is NOTCH2 p.Ser2379Phe (c.7136C>T) in the general population?

NOTCH2 p.Ser2379Phe (c.7136C>T) is ultra-rare (popmax 0.0171%, nfe) (gnomAD).

What do computational predictors say about NOTCH2 p.Ser2379Phe (c.7136C>T)?

AlphaMissense predicts ambiguous (score 0.3892) — an in-silico prediction, not a clinical call.

NOTCH2 p.Ser2379Phe

c.7136C>T · rs139595218 · VCV2197663

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3892 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, nfe)

Conditions

acroosteolysis dominant type

Computational evidence

Protein change
AlphaMissense	0.3892	ambiguous
REVEL	0.497	indeterminate
SaProt	LLR -8.06	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,256 bp · p 0.14 · regional, not allelic
Overall
CADD	24.9	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 0.0171% European (non-Finnish) · 202/1,180,048 alleles

Filtering AF 0.0152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0144%

Overall 0.0128% 207/1,613,922 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0171%	5,842
Remaining individualsnot grpmax-eligible	0.0032%	31,244
African / African-American	0.00267%	37,473
Admixed American	0.00167%	60,012

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.Ser2379Phe
Coding: c.7136C>T
MANE Select: NM_024408
dbSNP: rs139595218
Type: single nucleotide variant
Location: chr1:119915586 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 2379: a UniProt-annotated variant site (in hjcys); a UniProt-annotated variant site (in hjcys; loss of interaction with fbw7; decreased ubiquitination)

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

Also linked: Alagille syndrome due to a NOTCH2 point mutation

Similar variants

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
NOTCH2 c.874+4T>C 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-ser2379phe (accessed [today's date]).

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