Is NOTCH3 p.Cys511Arg (c.1531T>C) pathogenic?

NOTCH3 p.Cys511Arg (c.1531T>C) is classified Pathogenic/Likely pathogenic in NOTCH3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-08-20). AlphaMissense: likely pathogenic (0.9976); Absent from gnomAD v4.1; Associated with cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1.

How common is NOTCH3 p.Cys511Arg (c.1531T>C) in the general population?

NOTCH3 p.Cys511Arg (c.1531T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NOTCH3 p.Cys511Arg (c.1531T>C)?

AlphaMissense predicts likely pathogenic (score 0.9976) — an in-silico prediction, not a clinical call.

NOTCH3 p.Cys511Arg

Q: What condition is associated with NOTCH3 p.Cys511Arg (c.1531T>C)?

NOTCH3 p.Cys511Arg (c.1531T>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.1531T>C · VCV3380914

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9976 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,550,746)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9976	likely pathogenic ✓ concordant with ClinVar · top 3% in NOTCH3
REVEL	0.931	moderately pathogenic-leaning
SaProt	LLR -11.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 14 kb · p 4.2e-11 · regional, not allelic
Overall
CADD	28.9	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

No allele count reported in gnomAD v4.1 (AN 1,550,746). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: NOTCH3
Protein: p.Cys511Arg
Coding: c.1531T>C
MANE Select: NM_000435
Type: single nucleotide variant
Location: chr19:15187956 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 511: the egf-like 13; calcium-binding domain; a UniProt-annotated variant site (in cadasil1); a disulfide bond

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.Cys511Gly Pathogenic ★ same residue
NOTCH3 p.Cys511Trp Pathogenic ★ same residue
NOTCH3 p.Cys511Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
NOTCH3 p.Cys511Tyr 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

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-cys511arg (accessed [today's date]).

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