Is NOTCH3 p.Pro698Arg (c.2093C>G) pathogenic?

NOTCH3 p.Pro698Arg (c.2093C>G) is classified Uncertain significance in NOTCH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-15). AlphaMissense: likely benign (0.0868); Absent from gnomAD v4.1.

How common is NOTCH3 p.Pro698Arg (c.2093C>G) in the general population?

NOTCH3 p.Pro698Arg (c.2093C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NOTCH3 p.Pro698Arg (c.2093C>G)?

AlphaMissense predicts likely benign (score 0.0868) — an in-silico prediction, not a clinical call.

NOTCH3 p.Pro698Arg

c.2093C>G · rs2046874450 · VCV1708424

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0868 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0868	likely benign
REVEL	0.356	indeterminate
SaProt	LLR -9.13	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP -2.2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 8,846 bp · p 0.11 · regional, not allelic
Overall
CADD	22.4	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

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: NOTCH3
Protein: p.Pro698Arg
Coding: c.2093C>G
MANE Select: NM_000435
dbSNP: rs2046874450
Type: single nucleotide variant
Location: chr19:15185538 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 698: the egf-like 18 domain

Full NOTCH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NOTCH3 p.Pro698Ser Uncertain significance ★ ⚠ same residue
NOTCH3 c.341-2A>G Pathogenic ★★ same type
NOTCH3 c.341-2A>T Pathogenic ★★ same type
NOTCH3 p.Arg1006Cys Pathogenic ★★ ⚠ same type
NOTCH3 p.Arg1076Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
NOTCH3 p.Arg110Cys Pathogenic ★★ same type
NOTCH3 p.Arg133Cys Pathogenic/Likely pathogenic ★★ same type
NOTCH3 p.Arg141Cys Pathogenic ★★ same type

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/notch3-p-pro698arg (accessed [today's date]).

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