Is NOTCH2 p.Pro306= (c.918C>T) pathogenic?

NOTCH2 p.Pro306= (c.918C>T) is classified Likely benign in NOTCH2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-11-29). Very rare (popmax 0.00133%, afr); Associated with NOTCH2-related disorder.

What condition is associated with NOTCH2 p.Pro306= (c.918C>T)?

NOTCH2 p.Pro306= (c.918C>T) is associated with NOTCH2-related disorder (ClinVar).

How common is NOTCH2 p.Pro306= (c.918C>T) in the general population?

NOTCH2 p.Pro306= (c.918C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

NOTCH2 p.Pro306=

c.918C>T · rs1553200148 · VCV3059703

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

NOTCH2-related disorder

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 2.9	phastCons 1
Overall
CADD	9.122	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,910 alleles

Overall 6.2e-05% 1/1,613,992 alleles · very rare exomes 0/1,461,814 · genomes 1/152,178 · joint denominator

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: NOTCH2
Protein: p.Pro306=
Coding: c.918C>T
MANE Select: NM_024408
dbSNP: rs1553200148
Type: single nucleotide variant
Location: chr1:119969701 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 306: the egf-like 8; calcium-binding domain

Full NOTCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

NOTCH2-related disorder

Similar variants

NOTCH2 p.Pro306Ser Uncertain significance ★ ⚠ same residue
NOTCH2 p.Gln2263Ter Pathogenic ★★ same condition
NOTCH2 c.2753-8T>A Uncertain significance ★★ same condition
NOTCH2 p.Arg2036Gly Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Arg2051Gln Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Arg2060Cys Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Gly700Ser Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Gly700Val Uncertain significance ★★ ⚠ 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/notch2-p-pro306 (accessed [today's date]).

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