Is NOTCH2 p.Ala343= (c.1029C>T) pathogenic?

NOTCH2 p.Ala343= (c.1029C>T) is classified Uncertain significance in NOTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). Very rare (popmax 0.00223%, eas); Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Ala343= (c.1029C>T)?

NOTCH2 p.Ala343= (c.1029C>T) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Ala343= (c.1029C>T) in the general population?

NOTCH2 p.Ala343= (c.1029C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

NOTCH2 p.Ala343=

c.1029C>T · rs2526313169 · VCV2151340

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

acroosteolysis dominant type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Pangolin	Δ0.20	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.7	phastCons 1
Overall
CADD	16.74	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,858 alleles

Overall 6.2e-05% 1/1,614,058 alleles · very rare exomes 1/1,461,780 · genomes 0/152,278 · 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.Ala343=
Coding: c.1029C>T
MANE Select: NM_024408
dbSNP: rs2526313169
Type: single nucleotide variant
Location: chr1:119969590 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 343: the egf-like 9; calcium-binding domain

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

Disease context

acroosteolysis dominant type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOTCH2 p.Ala343Pro Uncertain significance ★ ⚠ same residue
NOTCH2 p.Ala343Thr Uncertain significance ★ ⚠ same residue
NOTCH2 p.Arg2003Ter Pathogenic/Likely pathogenic ★★ same condition
NOTCH2 p.Arg2400Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2223Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2263Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2285Ter Pathogenic/Likely pathogenic ★★ same condition
NOTCH2 c.2753-8T>A 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-ala343 (accessed [today's date]).

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