Is NOTCH2 p.Ser688= (c.2064C>T) pathogenic?

NOTCH2 p.Ser688= (c.2064C>T) is classified Likely benign in NOTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-25). Absent from gnomAD v4.1; Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Ser688= (c.2064C>T)?

NOTCH2 p.Ser688= (c.2064C>T) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Ser688= (c.2064C>T) in the general population?

NOTCH2 p.Ser688= (c.2064C>T) is absent from gnomAD v4.1 (gnomAD).

NOTCH2 p.Ser688=

c.2064C>T · rs2101124725 · VCV1558056

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,902)

Conditions

acroosteolysis dominant type

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 0.7	phastCons 1
Overall
CADD	11.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,613,902). 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: NOTCH2
Protein: p.Ser688=
Coding: c.2064C>T
MANE Select: NM_024408
dbSNP: rs2101124725
Type: single nucleotide variant
Location: chr1:119955195 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 688: a disulfide bond; the egf-like 18; 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.Ser688Phe Conflicting classifications of pathogenicity ★ ⚠ 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
NOTCH2 c.5214-10A>G 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-ser688 (accessed [today's date]).

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