Is NOTCH2 p.Phe1304= (c.3912C>T) pathogenic?

NOTCH2 p.Phe1304= (c.3912C>T) is classified Likely benign in NOTCH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-25). Ultra-rare (popmax 0.024%, afr); Associated with Alagille syndrome due to a NOTCH2 point mutation.

What condition is associated with NOTCH2 p.Phe1304= (c.3912C>T)?

NOTCH2 p.Phe1304= (c.3912C>T) is associated with Alagille syndrome due to a NOTCH2 point mutation, acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Phe1304= (c.3912C>T) in the general population?

NOTCH2 p.Phe1304= (c.3912C>T) is ultra-rare (popmax 0.024%, afr) (gnomAD).

NOTCH2 p.Phe1304=

c.3912C>T · rs764301517 · VCV1579947

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Conditions

Alagille syndrome due to a NOTCH2 point mutation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.37	acceptor gain · deltas
Pangolin	Δ0.32	gain · loss 0.26 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.85	phastCons 0.2
Overall
CADD	17.76	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% African / African-American · 18/74,858 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00267% 43/1,608,154 alleles · ultra-rare exomes 33/1,455,980 · genomes 10/152,174 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,159
South Asian	0.0167%	5,997
Admixed American	0.0151%	6,604
European (non-Finnish)	8.5e-05%	1,176,746

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.Phe1304=
Coding: c.3912C>T
MANE Select: NM_024408
dbSNP: rs764301517
Type: single nucleotide variant
Location: chr1:119926592 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 1304: the egf-like 34 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.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-phe1304 (accessed [today's date]).

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