Is NOTCH3 p.Pro2108= (c.6324G>A) pathogenic?

NOTCH3 p.Pro2108= (c.6324G>A) is classified Benign/Likely benign in NOTCH3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-27). Very rare (popmax 0.00919%, nfe).

How common is NOTCH3 p.Pro2108= (c.6324G>A) in the general population?

NOTCH3 p.Pro2108= (c.6324G>A) is very rare (popmax 0.00919%, nfe) (gnomAD).

NOTCH3 p.Pro2108=

c.6324G>A · rs776858941 · VCV741022

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00919%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.9	GERP -3.5
Overall
CADD	1.472	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00919% European (non-Finnish) · 105/1,142,116 alleles

Filtering AF 0.00774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00724%

Overall 0.00809% 124/1,532,344 alleles · very rare exomes 119/1,380,170 · genomes 5/152,174 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0152%	6,588
Finnishnot grpmax-eligible	0.0137%	7,275
European (non-Finnish)grpmax	0.00919%	10,877
Admixed American	0.0041%	24,393
South Asian	0.00123%	81,612

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.Pro2108=
Coding: c.6324G>A
MANE Select: NM_000435
dbSNP: rs776858941
Type: single nucleotide variant
Location: chr19:15161304 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 2108: a UniProt-annotated variant site (in carasil1; likely pathogenic); a UniProt-annotated variant site (in lmns; likely pathogenic); the 'disordered' region

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

Similar variants

NOTCH3 p.Pro2108Leu Uncertain significance ★★ same residue
NOTCH3 c.341-2A>G Pathogenic ★★ same type
NOTCH3 c.341-2A>T Pathogenic ★★ same type
NOTCH3 p.Arg1006Cys Pathogenic ★★ ⚠ same type
NOTCH3 p.Arg1076Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
NOTCH3 p.Arg110Cys Pathogenic ★★ same type
NOTCH3 p.Arg133Cys Pathogenic/Likely pathogenic ★★ same type
NOTCH3 p.Arg141Cys Pathogenic ★★ 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-pro2108 (accessed [today's date]).

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