Is NSD1 p.Ser975= (c.2925C>T) pathogenic?

NSD1 p.Ser975= (c.2925C>T) is classified Uncertain significance in NSD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2013-02-08). Ultra-rare (popmax 0.0164%, mid); Associated with Sotos syndrome.

What condition is associated with NSD1 p.Ser975= (c.2925C>T)?

NSD1 p.Ser975= (c.2925C>T) is associated with Sotos syndrome (ClinVar).

How common is NSD1 p.Ser975= (c.2925C>T) in the general population?

NSD1 p.Ser975= (c.2925C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Sotos syndrome inherited?

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

NSD1 p.Ser975=

c.2925C>T · rs587784090 · VCV159292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

Sotos syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.39	GERP -4.5
Overall
CADD	0.938	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000682% 11/1,613,948 alleles · ultra-rare exomes 9/1,461,880 · genomes 2/152,068 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.000678%	147,503

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: NSD1
Protein: p.Ser975=
Coding: c.2925C>T
MANE Select: NM_022455
dbSNP: rs587784090
Type: single nucleotide variant
Location: chr5:177211324 (GRCh38)
Gene constraint: LOEUF 0.144 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 45.26 · 4 PDB
Residue 975: the 'disordered' region

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.Ser975Pro Uncertain significance ★ ⚠ same residue
NSD1 c.1064-2A>G Pathogenic/Likely pathogenic ★★ same condition
NSD1 c.3921+1G>A Likely pathogenic ★★ same condition
NSD1 c.4192+2T>G Pathogenic ★★ same condition
NSD1 c.4378+1G>A Pathogenic/Likely pathogenic ★★ same condition
NSD1 c.4766-2A>G Pathogenic/Likely pathogenic ★★ same condition
NSD1 c.4966+1G>A Pathogenic ★★ same condition
NSD1 c.4966+1G>C Likely 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/nsd1-p-ser975 (accessed [today's date]).

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