Is NOTCH2 p.Pro484Ser (c.1450C>T) pathogenic?

NOTCH2 p.Pro484Ser (c.1450C>T) is classified Uncertain significance in NOTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-11). AlphaMissense: ambiguous (0.5355); Very rare (popmax 6.84e-05%); Associated with Alagille syndrome due to a NOTCH2 point mutation.

What condition is associated with NOTCH2 p.Pro484Ser (c.1450C>T)?

NOTCH2 p.Pro484Ser (c.1450C>T) is associated with Alagille syndrome due to a NOTCH2 point mutation (ClinVar).

How common is NOTCH2 p.Pro484Ser (c.1450C>T) in the general population?

NOTCH2 p.Pro484Ser (c.1450C>T) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about NOTCH2 p.Pro484Ser (c.1450C>T)?

AlphaMissense predicts ambiguous (score 0.5355) — an in-silico prediction, not a clinical call.

NOTCH2 p.Pro484Ser

c.1450C>T · VCV3376995

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5355 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Alagille syndrome due to a NOTCH2 point mutation

Computational evidence

Protein change
AlphaMissense	0.5355	ambiguous
REVEL	0.771	pathogenic-leaning
SaProt	LLR -9.20	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 46 kb · p 1.7e-32 · regional, not allelic
Overall
CADD	26.9	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 6.84e-05%

Overall 6.84e-05% 1/1,461,644 alleles · very rare

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.Pro484Ser
Coding: c.1450C>T
MANE Select: NM_024408
Type: single nucleotide variant
Location: chr1:119967436 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 484: a disulfide bond; the egf-like 12; calcium-binding 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

Similar variants

NOTCH2 p.Arg2400Ter Pathogenic ★★ same condition
NOTCH2 c.5214-10A>G Uncertain significance ★★ same condition
NOTCH2 p.Ala1154Val Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Ala1340Val Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Ala1797Val Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Ala2018Ser Uncertain significance ★★ same condition
NOTCH2 p.Ala2198Thr Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Ala2333Val 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-pro484ser (accessed [today's date]).

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