Is NOTCH2 p.Phe1406Ser (c.4217T>C) pathogenic?

NOTCH2 p.Phe1406Ser (c.4217T>C) is classified Uncertain significance in NOTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: ambiguous (0.543); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with NOTCH2 p.Phe1406Ser (c.4217T>C)?

NOTCH2 p.Phe1406Ser (c.4217T>C) is associated with Inborn genetic diseases (ClinVar).

How common is NOTCH2 p.Phe1406Ser (c.4217T>C) in the general population?

NOTCH2 p.Phe1406Ser (c.4217T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NOTCH2 p.Phe1406Ser (c.4217T>C)?

AlphaMissense predicts ambiguous (score 0.543) — an in-silico prediction, not a clinical call.

NOTCH2 p.Phe1406Ser

c.4217T>C · VCV3921081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.543 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.543	ambiguous
REVEL	0.232	benign-leaning
SaProt	LLR -9.66	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 40 kb · p 1.4e-18 · regional, not allelic
Overall
CADD	23.6	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.Phe1406Ser
Coding: c.4217T>C
MANE Select: NM_024408
Type: single nucleotide variant
Location: chr1:119925599 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 1406: a disulfide bond; the egf-like 35 domain

Full NOTCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOTCH2 p.Arg2003Ter Pathogenic/Likely pathogenic ★★ same condition
NOTCH2 p.Ala1416Gly Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Arg1231Gln Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Arg1231Trp Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Arg1718His Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Arg1801Ser Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Arg1824Cys Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Arg2104Gly 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-phe1406ser (accessed [today's date]).

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