Is NOTCH3 p.Ala40= (c.120C>G) pathogenic?

NOTCH3 p.Ala40= (c.120C>G) is classified Conflicting classifications of pathogenicity in NOTCH3 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-02). Ultra-rare (popmax 0.0117%, amr); Associated with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy.

What condition is associated with NOTCH3 p.Ala40= (c.120C>G)?

NOTCH3 p.Ala40= (c.120C>G) is associated with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (ClinVar).

How common is NOTCH3 p.Ala40= (c.120C>G) in the general population?

NOTCH3 p.Ala40= (c.120C>G) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

NOTCH3 p.Ala40=

c.120C>G · rs146904189 · VCV256119

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Conditions

cerebral arteriopathy with subcortical infarcts and leukoencephalopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.48	GERP -2.4, phastCons 0.004
Overall
CADD	3.581	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,924 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.0018% 29/1,611,276 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,561
African / African-American	0.00668%	14,976
Remaining individualsnot grpmax-eligible	0.0016%	62,356
European (non-Finnish)	0.00136%	73,734

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.Ala40=
Coding: c.120C>G
MANE Select: NM_000435
dbSNP: rs146904189
Type: single nucleotide variant
Location: chr19:15197577 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 40: the egf-like 1 domain

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

Disease context

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

Similar variants

NOTCH3 p.Ala40Val Uncertain significance ★★ ⚠ same residue
NOTCH3 p.Arg207Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
NOTCH3 p.Arg544Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
NOTCH3 p.Arg54Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
NOTCH3 p.Arg578Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
NOTCH3 p.Cys194Tyr Pathogenic ★★ same condition
NOTCH3 p.Cys233Tyr Pathogenic/Likely pathogenic ★★ same condition
NOTCH3 p.Asp45His 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/notch3-p-ala40 (accessed [today's date]).

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