SMYD3

Chr 1

SET and MYND domain containing 3

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

NCBI Gene: 64754ENSG00000185420UniProt: Q9H7B4

This gene encodes a histone methyltransferase which functions in RNA polymerase II complexes by an interaction with a specific RNA helicase. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

241
ClinVar variants
81
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SMYD3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
81 Pathogenic / Likely Pathogenic· 115 VUS of 241 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.90LOEUF
pLI 0.000
Z-score 1.96
OE 0.58 (0.39–0.90)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.24Z-score
OE missense 0.96 (0.86–1.07)
225 obs / 235.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.58 (0.39–0.90)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.96 (0.86–1.07)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01
0≤1.21.6
LoF obs/exp: 15 / 25.7Missense obs/exp: 225 / 235.6Syn Z: -0.04

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Smyd3-associated regulatory pathways in cancer.
Giakountis A et al.·Semin Cancer Biol
2017Review
Clinicopathological and Prognostic Significance of SMYD3 in Human Cancers: A Systematic Review and Meta-analysis.
Wang X et al.·Genet Test Mol Biomarkers
2022Meta-analysis
Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCC.
Wang S et al.·J Adv Res
2025
Upregulation of SMYD3 and SMYD3 VNTR 3/3 polymorphism increase the risk of hepatocellular carcinoma.
Binh MT et al.·Sci Rep
2020
Chemoprevention of hepatocellular carcinoma using N-acetylgalactosamine-conjugated siRNAs.
Maggiore G et al.·Dis Model Mech
2025
Lysine methylation in cancer: SMYD3-MAP3K2 teaches us new lessons in the Ras-ERK pathway.
Colón-Bolea P et al.·Bioessays
2014Review
SMYD3-NY, a novel SMYD3 mRNA transcript variant, may have a role in human spermatogenesis.
Zhou Z et al.·Ann Clin Lab Sci
2005
SMYD3 promotes the epithelial-mesenchymal transition in breast cancer.
Fenizia C et al.·Nucleic Acids Res
2019
Overexpression of SMYD3 Is Predictive of Unfavorable Prognosis in Hepatocellular Carcinoma.
Fei X et al.·Tohoku J Exp Med
2017
Functions of SMYD proteins in biological processes: What do we know? An updated review.
Rueda-Robles A et al.·Arch Biochem Biophys
2021Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
SMYD3 synergises with RACK1 to promote colorectal cancer lung metastasis by recruiting SMAD3.
Bai X et al.·Cell Commun Signal
2026🔓 Open Access
Glycogen for Smyd3-antisense oligonucleotide delivery and enhanced liver cancer gene therapy.
Bai N et al.·RSC Adv
2025🔓 Open Access
Grass carp (Ctenopharyngodon idella) SMYD3 negatively regulates antiviral innate immunity by methylating IRF3 and IRF7 during GCRV infection.
Wang Z et al.·J Immunol
2025
SMYD3-CDCP1 Axis Drives EMT and CAF Activation in Colorectal Cancer and Is Targetable for Oxaliplatin Sensitization.
Zhao L et al.·Biomedicines
2025🔓 Open Access
Loss of histone methyltransferase Smyd3 triggers WAT browning and adaptive thermogenesis via enhancing PPARγ expression in a H4K20me3-dependent manner.
Shu M et al.·J Transl Med
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools