Is NOTCH3 p.Pro2178fs (c.6530dup) pathogenic?

NOTCH3 p.Pro2178fs (c.6530dup) is classified Likely pathogenic in NOTCH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-01). Absent from gnomAD v4.1.

How common is NOTCH3 p.Pro2178fs (c.6530dup) in the general population?

NOTCH3 p.Pro2178fs (c.6530dup) is absent from gnomAD v4.1 (gnomAD).

NOTCH3 p.Pro2178fs

c.6530dup · VCV3772368

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,537,306)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (33 of 33) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -5.8	GERP -3.5

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,537,306). 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.Pro2178fs
Coding: c.6530dup
MANE Select: NM_000435
Type: Duplication
Location: chr19:15161097 (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

Similar variants

NOTCH3 p.Pro2178Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
NOTCH3 p.Ala2233fs Pathogenic ★★ same type
NOTCH3 p.Cys76_Gln77insArgValGlyGluArgCys Pathogenic/Likely pathogenic ★★ same type
NOTCH3 p.Gly1329fs Pathogenic/Likely pathogenic ★★ same type
NOTCH3 p.Pro2210fs Pathogenic/Likely pathogenic ★★ same type
NOTCH3 p.Asn2197_Pro2198insLeuAsn Uncertain significance ★★ same type
NOTCH3 p.Gln800fs Uncertain significance ★★ same type
NOTCH3 p.Ser1335dup Uncertain significance ★★ same type

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-pro2178fs (accessed [today's date]).

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