Is NOTCH3 p.Arg640= (c.1920C>T) pathogenic?

NOTCH3 p.Arg640= (c.1920C>T) is classified Likely benign in NOTCH3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-12-27). Ultra-rare (popmax 0.0164%, nfe); Associated with cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1.

How common is NOTCH3 p.Arg640= (c.1920C>T) in the general population?

NOTCH3 p.Arg640= (c.1920C>T) is ultra-rare (popmax 0.0164%, nfe) (gnomAD).

NOTCH3 p.Arg640=

Q: What condition is associated with NOTCH3 p.Arg640= (c.1920C>T)?

NOTCH3 p.Arg640= (c.1920C>T) is associated with cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (ClinVar).

Q: How is Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1920C>T · rs140818133 · VCV447801

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, nfe)

Conditions

cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.4	GERP -0.2, phastCons 1
Overall
CADD	9.822	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% European (non-Finnish) · 193/1,180,042 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.0126% 203/1,614,102 alleles · ultra-rare exomes 195/1,461,872 · genomes 8/152,230 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0164%	6,114
Remaining individualsnot grpmax-eligible	0.0096%	10,415
Finnishnot grpmax-eligible	0.00312%	32,016
Admixed American	0.00167%	60,008
African / African-American	0.00133%	74,942

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: NOTCH3
Protein: p.Arg640=
Coding: c.1920C>T
MANE Select: NM_000435
dbSNP: rs140818133
Type: single nucleotide variant
Location: chr19:15186909 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 640: the egf-like 16; calcium-binding domain

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

Disease context

cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

NOTCH3 p.Arg640Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
NOTCH3 p.Arg640His Conflicting classifications of pathogenicity ★ ⚠ same residue
NOTCH3 c.341-2A>T Pathogenic ★★ same condition
NOTCH3 p.Arg1006Cys Pathogenic ★★ ⚠ same condition
NOTCH3 p.Arg1076Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
NOTCH3 p.Arg110Cys Pathogenic ★★ same condition
NOTCH3 p.Arg133Cys Pathogenic/Likely pathogenic ★★ same condition
NOTCH3 p.Arg141Cys Pathogenic ★★ 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/notch3-p-arg640 (accessed [today's date]).

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