SMYD3

Chr 1

SET and MYND domain containing 3

Also known as: KMT3E, ZMYND1, ZNFN3A1, bA74P14.1

NCBI Gene: 64754ENSG00000185420UniProt: Q9H7B4OMIM: 608783

This gene encodes a histone methyltransferase that specifically methylates lysine-4 of histone H3 and lysine-5 of histone H4, functioning as part of RNA polymerase II complexes to regulate transcriptional activation. Mutations cause autosomal dominant developmental delays and intellectual disability with onset in early childhood. The gene is not highly constrained against loss-of-function variants.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 0.90
Clinical Summary— SMYD3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
81 unique Pathogenic / Likely Pathogenic· 115 VUS of 241 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.90LOEUF
pLI 0.000
Z-score 1.96
OE 0.58 (0.39–0.90)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.24Z-score
OE missense 0.96 (0.86–1.07)
225 obs / 235.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.58 (0.39–0.90)
0≤0.351.4
Missense OE0.96 (0.86–1.07)
0≤0.61.4
Synonymous OE1.01
0≤1.21.6
LoF obs/exp: 15 / 25.7Missense obs/exp: 225 / 235.6Syn Z: -0.04
DN
0.6744th %ile
GOF
0.6931th %ile
LOF
0.2386th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

241 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic74
Likely Pathogenic7
VUS115
Likely Benign18
Benign4
74
Pathogenic
7
Likely Pathogenic
115
VUS
18
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
74
0
74
Likely Pathogenic
0
0
7
0
7
VUS
0
61
54
0
115
Likely Benign
0
0
18
0
18
Benign
0
0
3
1
4
Total0611561218

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

View in ClinVar →

Protein Context — Lollipop Plot

SMYD3 · 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
Predictive bioactivity modeling and structural binding analysis for the identification of potential SMYD3 modulators.
Alzahrani AR et al.·Mol Divers
2026Functional
Grass carp (Ctenopharyngodon idella) SMYD3 negatively regulates antiviral innate immunity by methylating IRF3 and IRF7 during GCRV infection.
Wang Z et al.·J Immunol
2026
SMYD3 synergises with RACK1 to promote colorectal cancer lung metastasis by recruiting SMAD3.
Bai X et al.·Cell Commun Signal
2026Open Access
Macrophage-Derived Transcriptional Signatures Predict Prognosis and Drug Sensitivity in Thyroid Cancer: Integrative Analysis and Experimental Validation of SMYD3.
Xu S et al.·Immunotargets Ther
2026Open Access
Glycogen for Smyd3-antisense oligonucleotide delivery and enhanced liver cancer gene therapy.
Bai N et al.·RSC Adv
2025Open Access
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