Is NOTCH3 p.Pro2178Ser (c.6532C>T) pathogenic?

NOTCH3 p.Pro2178Ser (c.6532C>T) is classified Conflicting classifications of pathogenicity in NOTCH3 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-06-26). AlphaMissense: likely benign (0.0903); Rare (popmax 0.226%, amr); Associated with cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1.

How common is NOTCH3 p.Pro2178Ser (c.6532C>T) in the general population?

NOTCH3 p.Pro2178Ser (c.6532C>T) is rare (popmax 0.226%, amr) (gnomAD).

What do computational predictors say about NOTCH3 p.Pro2178Ser (c.6532C>T)?

AlphaMissense predicts likely benign (score 0.0903) — an in-silico prediction, not a clinical call.

NOTCH3 p.Pro2178Ser

Q: What condition is associated with NOTCH3 p.Pro2178Ser (c.6532C>T)?

NOTCH3 p.Pro2178Ser (c.6532C>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.6532C>T · rs751951476 · VCV328372

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0903 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.226%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0903	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -7.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 0.65, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 947 bp · p 0.67 · regional, not allelic
Overall
CADD	21.1	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 0.226% Admixed American · 116/51,262 alleles

Filtering AF 0.193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.18%

Overall 0.0398% 613/1,541,304 alleles · rare exomes 528/1,388,998 · genomes 85/152,306 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.226%	442
Remaining individualsnot grpmax-eligible	0.0615%	1,625
European (non-Finnish)	0.0396%	2,526
African / African-American	0.00681%	14,689

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.Pro2178Ser
Coding: c.6532C>T
MANE Select: NM_000435
dbSNP: rs751951476
Type: single nucleotide variant
Location: chr19:15161096 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 2178: a UniProt-annotated variant site (in carasil1; likely pathogenic); a UniProt-annotated variant site (in lmns; likely pathogenic)

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 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
NOTCH3 p.Arg153Cys Pathogenic ★★ same condition
NOTCH3 p.Arg169Cys Pathogenic/Likely 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-pro2178ser (accessed [today's date]).

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