Is NOTCH3 p.Ser299= (c.897C>T) pathogenic?

NOTCH3 p.Ser299= (c.897C>T) is classified Conflicting classifications of pathogenicity in NOTCH3 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2023-02-20). Very rare (popmax 0.0011%, sas); Associated with NOTCH3-related disorder.

What condition is associated with NOTCH3 p.Ser299= (c.897C>T)?

NOTCH3 p.Ser299= (c.897C>T) is associated with NOTCH3-related disorder, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 (ClinVar).

How common is NOTCH3 p.Ser299= (c.897C>T) in the general population?

NOTCH3 p.Ser299= (c.897C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

NOTCH3 p.Ser299=

c.897C>T · rs768851285 · VCV3049003

Conflicting classifications of pathogenicity No assertion criteria

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

NOTCH3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.60 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 1.9, phastCons 1
Overall
CADD	13.43	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,082 alleles

Overall 0.000186% 3/1,613,672 alleles · very rare exomes 3/1,461,306 · genomes 0/152,366 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,502
South Asiangrpmax	0.0011%	91,082
European (non-Finnish)	8.47e-05%	1,180,045

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser299=
Coding: c.897C>T
MANE Select: NM_000435
dbSNP: rs768851285
Type: single nucleotide variant
Location: chr19:15191563 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 299: the egf-like 7 domain

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

Disease context

NOTCH3-related disorder

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

Similar variants

NOTCH3 p.Ser299Cys 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
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-ser299 (accessed [today's date]).

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