Is NOTCH3 p.Ser550Phe (c.1649C>T) pathogenic?

NOTCH3 p.Ser550Phe (c.1649C>T) is classified Uncertain significance in NOTCH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-07-02). AlphaMissense: likely benign (0.1293); Ultra-rare (popmax 0.0156%, eas); Associated with cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1.

How common is NOTCH3 p.Ser550Phe (c.1649C>T) in the general population?

NOTCH3 p.Ser550Phe (c.1649C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about NOTCH3 p.Ser550Phe (c.1649C>T)?

AlphaMissense predicts likely benign (score 0.1293) — an in-silico prediction, not a clinical call.

NOTCH3 p.Ser550Phe

Q: What condition is associated with NOTCH3 p.Ser550Phe (c.1649C>T)?

NOTCH3 p.Ser550Phe (c.1649C>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.1649C>T · rs1210611177 · VCV892108

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1293 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.1293	likely benign
REVEL	0.324	indeterminate
SaProt	LLR -9.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -0.86, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 14 kb · p 4.2e-11 · regional, not allelic
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,886 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.000496% 8/1,614,026 alleles · ultra-rare exomes 8/1,461,686 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,412
European (non-Finnish)	8.47e-05%	1,180,020

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.Ser550Phe
Coding: c.1649C>T
MANE Select: NM_000435
dbSNP: rs1210611177
Type: single nucleotide variant
Location: chr19:15187296 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 550: the egf-like 14; 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.Ser550= 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
NOTCH3 p.Arg153Cys 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-ser550phe (accessed [today's date]).

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