Is NOTCH2 p.Cys412Phe (c.1235G>T) pathogenic?

NOTCH2 p.Cys412Phe (c.1235G>T) is classified Likely pathogenic in NOTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-01). AlphaMissense: likely pathogenic (0.9991); Absent from gnomAD v4.1; Associated with Alagille syndrome due to a NOTCH2 point mutation.

What condition is associated with NOTCH2 p.Cys412Phe (c.1235G>T)?

NOTCH2 p.Cys412Phe (c.1235G>T) is associated with Alagille syndrome due to a NOTCH2 point mutation (ClinVar).

How common is NOTCH2 p.Cys412Phe (c.1235G>T) in the general population?

NOTCH2 p.Cys412Phe (c.1235G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NOTCH2 p.Cys412Phe (c.1235G>T)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

NOTCH2 p.Cys412Phe

c.1235G>T · VCV4528331

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Alagille syndrome due to a NOTCH2 point mutation

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic ✓ concordant with ClinVar · top 1% in NOTCH2
REVEL	0.915	moderately pathogenic-leaning
SaProt	LLR -10.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 46 kb · p 1.7e-32 · regional, not allelic
Overall
CADD	26.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NOTCH2
Protein: p.Cys412Phe
Coding: c.1235G>T
MANE Select: NM_024408
Type: single nucleotide variant
Location: chr1:119968106 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 412: a disulfide bond; the egf-like 10 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.Cys412Ser Uncertain significance ★ ⚠ same residue
NOTCH2 p.Cys412= Likely benign ★ same residue
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

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-cys412phe (accessed [today's date]).

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