Is NOTCH2 p.Val640Phe (c.1918G>T) pathogenic?

NOTCH2 p.Val640Phe (c.1918G>T) is classified Uncertain significance in NOTCH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-19). AlphaMissense: likely benign (0.1201); Very rare (popmax 0.00167%, amr); Associated with Alagille syndrome due to a NOTCH2 point mutation.

What condition is associated with NOTCH2 p.Val640Phe (c.1918G>T)?

NOTCH2 p.Val640Phe (c.1918G>T) is associated with Alagille syndrome due to a NOTCH2 point mutation, acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Val640Phe (c.1918G>T) in the general population?

NOTCH2 p.Val640Phe (c.1918G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about NOTCH2 p.Val640Phe (c.1918G>T)?

AlphaMissense predicts likely benign (score 0.1201) — an in-silico prediction, not a clinical call.

NOTCH2 p.Val640Phe

c.1918G>T · VCV3588704

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1201 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Alagille syndrome due to a NOTCH2 point mutation

Computational evidence

Protein change
AlphaMissense	0.1201	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -7.86	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 0.58	phastCons 0.092
Regional constraint	o/e 0.57	unconstrained · MANE · 46 kb · p 1.7e-32 · regional, not allelic
Overall
CADD	12.59	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 0.00167% Admixed American · 1/59,922 alleles

Filtering AF 0.000376% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000272%

Overall 0.000643% 10/1,554,208 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,922
European (non-Finnish)	0.0008%	125,072

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.Val640Phe
Coding: c.1918G>T
MANE Select: NM_024408
Type: single nucleotide variant
Location: chr1:119959500 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 640: a disulfide bond; the egf-like 16; 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

Also linked: acroosteolysis dominant type

Similar variants

NOTCH2 p.Val640Ile Uncertain significance ★★ ⚠ same residue
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

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-val640phe (accessed [today's date]).

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