NSD2

Chr 4AD

nuclear receptor binding SET domain protein 2

Also known as: KMT3F, KMT3G, MMSET, RAUST, REIIBP, TRX5, WHS, WHSC1

NCBI Gene: 7468ENSG00000109685UniProt: O96028OMIM: 602952

The protein encoded by this gene is a histone methyltransferase that contains PWWP, HMG box, SET, and PHD domains and functions in chromatin modification during early development. Loss-of-function mutations cause Rauch-Steindl syndrome through an autosomal dominant inheritance pattern. The gene is also located within the Wolf-Hirschhorn syndrome critical region on chromosome 4p16.3 and contributes to the malformation phenotype seen with deletions of this chromosomal region.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismADLOEUF 0.121 OMIM phenotype
Clinical Summary— NSD2
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Gene-Disease Validity (ClinGen)
syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
158 unique Pathogenic / Likely Pathogenic· 314 VUS of 800 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.12LOEUF
pLI 1.000
Z-score 7.14
OE 0.05 (0.02–0.12)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
3.90Z-score
OE missense 0.61 (0.57–0.66)
498 obs / 810.2 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.05 (0.02–0.12)
0≤0.351.4
Missense OE0.61 (0.57–0.66)
0≤0.61.4
Synonymous OE1.14
0≤1.21.6
LoF obs/exp: 3 / 65.3Missense obs/exp: 498 / 810.2Syn Z: -1.94
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongNSD2-related developmental disorderLOFAD
DN
0.2698th %ile
GOF
0.2497th %ile
LOF
0.82top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 36% of P/LP variants are LoF · LOEUF 0.12

Literature Evidence

LOFNSD2 haploinsufficiency causes Wolf-Hirschhorn syndrome, while NSD1 mutations lead to the Sotos syndrome.PMID:25942451

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

800 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic114
Likely Pathogenic44
VUS314
Likely Benign238
Benign29
Conflicting26
114
Pathogenic
44
Likely Pathogenic
314
VUS
238
Likely Benign
29
Benign
26
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
38
5
71
0
114
Likely Pathogenic
19
15
9
1
44
VUS
9
271
30
4
314
Likely Benign
2
51
61
124
238
Benign
0
3
19
7
29
Conflicting
—26
Total68345190136765

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

NSD2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients