Is NSD1 p.Pro2136fs (c.6405dup) pathogenic?

NSD1 p.Pro2136fs (c.6405dup) is classified Pathogenic in NSD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-22). Associated with Sotos syndrome.

What condition is associated with NSD1 p.Pro2136fs (c.6405dup)?

NSD1 p.Pro2136fs (c.6405dup) is associated with Sotos syndrome (ClinVar).

How is Sotos syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

NSD1 p.Pro2136fs

c.6405dup · VCV4531986

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

Sotos syndrome

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 22 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP -2, phastCons 1

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

Variant & gene context

Gene: NSD1
Protein: p.Pro2136fs
Coding: c.6405dup
MANE Select: NM_022455
Type: Duplication
Location: chr5:177292097 (GRCh38)
Gene constraint: LOEUF 0.144 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 45.26 · 4 PDB

Full NSD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Sotos syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sotos syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

NSD1 p.Asn576fs Pathogenic ★★ same condition
NSD1 p.Asp1428fs Pathogenic ★★ same condition
NSD1 p.Cys2146fs Pathogenic/Likely pathogenic ★★ same condition
NSD1 p.Glu1184Ter Pathogenic ★★ same condition
NSD1 p.Ile538fs Pathogenic ★★ same condition
NSD1 p.Met1531fs Pathogenic/Likely pathogenic ★★ same condition
NSD1 c.4966+96dup Benign/Likely benign ★★ same condition
NSD1 p.Pro2136= Likely benign ★★ same residue

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/nsd1-p-pro2136fs (accessed [today's date]).

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