Is NOTCH2 p.Val2139Phe (c.6415G>T) pathogenic?

NOTCH2 p.Val2139Phe (c.6415G>T) is classified Uncertain significance in NOTCH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-14). AlphaMissense: likely benign (0.1048); Very rare (popmax 0.000169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NOTCH2 p.Val2139Phe (c.6415G>T)?

NOTCH2 p.Val2139Phe (c.6415G>T) is associated with Inborn genetic diseases (ClinVar).

How common is NOTCH2 p.Val2139Phe (c.6415G>T) in the general population?

NOTCH2 p.Val2139Phe (c.6415G>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about NOTCH2 p.Val2139Phe (c.6415G>T)?

AlphaMissense predicts likely benign (score 0.1048) — an in-silico prediction, not a clinical call.

NOTCH2 p.Val2139Phe

c.6415G>T · VCV4861130

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1048 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1048	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,256 bp · p 0.14 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,026 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,892 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.Val2139Phe
Coding: c.6415G>T
MANE Select: NM_024408
Type: single nucleotide variant
Location: chr1:119916307 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 2139: the 'disordered' region

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-val2139phe (accessed [today's date]).

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