Is NSD1 p.Leu2425= (c.7275A>G) pathogenic?

NSD1 p.Leu2425= (c.7275A>G) is classified Benign/Likely benign in NSD1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-14). Rare (popmax 0.1%, eas); Associated with Sotos syndrome.

What condition is associated with NSD1 p.Leu2425= (c.7275A>G)?

NSD1 p.Leu2425= (c.7275A>G) is associated with Sotos syndrome (ClinVar).

How common is NSD1 p.Leu2425= (c.7275A>G) in the general population?

NSD1 p.Leu2425= (c.7275A>G) is rare (popmax 0.1%, eas) (gnomAD).

How is Sotos syndrome inherited?

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

NSD1 p.Leu2425=

c.7275A>G · rs139879749 · VCV261595

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.1%, eas)

Conditions

Sotos syndrome

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 -4.8	GERP -4.2
Overall
CADD	0.067	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.1% East Asian · 45/44,892 alleles

Filtering AF 0.077% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0688%

Overall 0.00427% 69/1,614,226 alleles · rare exomes 56/1,461,892 · genomes 13/152,334 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.1%	998
African / African-American	0.0107%	9,381
European (non-Finnish)	0.00127%	78,670
South Asian	0.0011%	91,086

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.Leu2425=
Coding: c.7275A>G
MANE Select: NM_022455
dbSNP: rs139879749
Type: single nucleotide variant
Location: chr5:177294643 (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 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
NSD1 c.5146+1G>A Pathogenic/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-leu2425 (accessed [today's date]).

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