Is NOTCH1 p.Ser1970fs (c.5906dup) pathogenic?

NOTCH1 p.Ser1970fs (c.5906dup) is classified Pathogenic in NOTCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-08). Absent from gnomAD; Associated with Adams-Oliver syndrome 5.

What condition is associated with NOTCH1 p.Ser1970fs (c.5906dup)?

NOTCH1 p.Ser1970fs (c.5906dup) is associated with Adams-Oliver syndrome 5 (ClinVar).

How common is NOTCH1 p.Ser1970fs (c.5906dup) in the general population?

NOTCH1 p.Ser1970fs (c.5906dup) is absent from gnomAD (gnomAD).

NOTCH1 p.Ser1970fs

c.5906dup · rs2540427371 · VCV2844046

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Adams-Oliver syndrome 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 31 of 34
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.67	GERP -4.5

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. 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: NOTCH1
Protein: p.Ser1970fs
Coding: c.5906dup
MANE Select: NM_017617
dbSNP: rs2540427371
Type: Duplication
Location: chr9:136500579 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 1970: an α-helix

Full NOTCH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Adams-Oliver syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOTCH1 p.Cys817fs Pathogenic ★★ same condition
NOTCH1 p.Tyr550Ter Pathogenic ★★ same condition
NOTCH1 p.Ala973fs Pathogenic ★ same condition
NOTCH1 p.Glu601fs Pathogenic ★ same condition
NOTCH1 p.Gly1772fs Pathogenic ★ same condition
NOTCH1 p.Met1580fs Pathogenic ★ same condition
NOTCH1 p.Met2318fs Likely pathogenic ★ same condition
NOTCH1 p.Ser921fs Pathogenic ★ 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/notch1-p-ser1970fs (accessed [today's date]).

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