Is NOTCH3 p.Ser135Pro (c.403T>C) pathogenic?

NOTCH3 p.Ser135Pro (c.403T>C) is classified Uncertain significance in NOTCH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-22). AlphaMissense: likely pathogenic (0.6247); Absent from gnomAD v4.1; Associated with cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1.

How common is NOTCH3 p.Ser135Pro (c.403T>C) in the general population?

NOTCH3 p.Ser135Pro (c.403T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NOTCH3 p.Ser135Pro (c.403T>C)?

AlphaMissense predicts likely pathogenic (score 0.6247) — an in-silico prediction, not a clinical call.

NOTCH3 p.Ser135Pro

Q: What condition is associated with NOTCH3 p.Ser135Pro (c.403T>C)?

NOTCH3 p.Ser135Pro (c.403T>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.403T>C · rs2145442354 · VCV1526178

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6247 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

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	0.6247	likely pathogenic
REVEL	0.667	pathogenic-leaning
SaProt	LLR -11.54	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 5.1	GERP -0.35, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 14 kb · p 4.2e-11 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NOTCH3
Protein: p.Ser135Pro
Coding: c.403T>C
MANE Select: NM_000435
dbSNP: rs2145442354
Type: single nucleotide variant
Location: chr19:15192236 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 135: the egf-like 3 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 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-ser135pro (accessed [today's date]).

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