Is NOTCH3 p.Arg75Pro (c.224G>C) pathogenic?

NOTCH3 p.Arg75Pro (c.224G>C) is classified Pathogenic/Likely pathogenic in NOTCH3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-13). AlphaMissense: likely benign (0.2938); Ultra-rare (popmax 0.0204%, eas); Associated with cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1.

How common is NOTCH3 p.Arg75Pro (c.224G>C) in the general population?

NOTCH3 p.Arg75Pro (c.224G>C) is ultra-rare (popmax 0.0204%, eas) (gnomAD).

What do computational predictors say about NOTCH3 p.Arg75Pro (c.224G>C)?

AlphaMissense predicts likely benign (score 0.2938) — an in-silico prediction, not a clinical call.

NOTCH3 p.Arg75Pro

Q: What condition is associated with NOTCH3 p.Arg75Pro (c.224G>C)?

NOTCH3 p.Arg75Pro (c.224G>C) 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.224G>C · rs145069047 · VCV632306

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2938 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0204%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.2938	likely benign ⚠ discordant with ClinVar
REVEL	0.68	pathogenic-leaning
SaProt	LLR -13.72	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.66, phastCons 0.1
Regional constraint	o/e 0.78	unconstrained · MANE · 14 kb · p 4.2e-11 · regional, not allelic
Overall
CADD	21.6	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

Grpmax group 0.0204% East Asian · 9/44,198 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0079%

Overall 0.000562% 9/1,600,058 alleles · ultra-rare exomes 8/1,448,072 · genomes 1/151,986 · joint denominator

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.Arg75Pro
Coding: c.224G>C
MANE Select: NM_000435
dbSNP: rs145069047
Type: single nucleotide variant
Location: chr19:15192493 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 75: the egf-like 1 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.Arg75Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
NOTCH3 p.Arg75Trp Benign/Likely benign ★★ ⚠ 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-arg75pro (accessed [today's date]).

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