SYN3

Chr 22

synapsin III

NCBI Gene: 8224ENSG00000185666UniProt: O14994

This gene is a member of the synapsin gene family. Synapsins encode neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. The protein encoded by this gene shares the synapsin family domain model, with domains A, C, and E exhibiting the highest degree of conservation. The protein contains a unique domain J, located between domains C and E. Based on this gene's localization to 22q12.3, a possible schizophrenia susceptibility locus, and the established neurobiological roles of the synapsins, this family member may represent a candidate gene for schizophrenia. The TIMP3 gene is located within an intron of this gene and is transcribed in the opposite direction. Alternative splicing of this gene results in multiple splice variants that encode different isoforms. [provided by RefSeq, Oct 2008]

407
ClinVar variants
28
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— SYN3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.35) despite low pLI — interpret in context.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 222 VUS of 407 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.59LOEUF
pLI 0.002
Z-score 3.26
OE 0.35 (0.21–0.59)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
1.04Z-score
OE missense 0.84 (0.76–0.93)
289 obs / 343.0 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.0.35 (0.21–0.59)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.84 (0.76–0.93)
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.0.79
0≤1.21.6
LoF obs/exp: 10 / 28.9Missense obs/exp: 289 / 343.0Syn Z: 1.96

ClinVar Variant Classifications

407 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic5
VUS222
Likely Benign83
Benign44
Conflicting10
23
Pathogenic
5
Likely Pathogenic
222
VUS
83
Likely Benign
44
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
8
15
0
23
Likely Pathogenic
0
3
2
0
5
VUS
0
145
76
1
222
Likely Benign
0
10
26
47
83
Benign
0
4
33
7
44
Conflicting
—10
Total017015255387

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

View in ClinVar →

Protein Context — Lollipop Plot

SYN3 · 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
SYNAPSIN III; SYN3
MIM #602705 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.
Boorjian SA et al.·Lancet Oncol
2021Clinical trial
Enhancement of intravesical delivery with Syn3 potentiates interferon-alpha2b gene therapy for superficial bladder cancer.
Nagabhushan TL et al.·Cytokine Growth Factor Rev
2007Review
Uterine leiomyoma-like inflammatory myofibroblastic tumour with a rare ALK::SYN3 fusion: a clinicopathologic and molecular analysis.
Ma C et al.·Diagn Pathol
2025Review
Gene-mediated therapy for BCG-unresponsive nonmuscle-invasive bladder cancer: mechanisms, clinical evidence, and practical implementation.
Wong CH et al.·Curr Opin Urol
2025Review
Inflammatory myofibroblastic tumors associated with the placenta: a series of 9 cases.
Makhdoum S et al.·Hum Pathol
2020Review
Intravesical interferon-α2b gene therapy with nadofaragene firadenovec-vncg: a contemporary review.
Lee T et al.·Future Oncol
2025Review
Phase I trial of intravesical recombinant adenovirus mediated interferon-α2b formulated in Syn3 for Bacillus Calmette-Guérin failures in nonmuscle invasive bladder cancer.
Dinney CP et al.·J Urol
2013Clinical trial
Interferon gene therapy with nadofaragene firadenovec for bladder cancer: from bench to approval.
Martini A et al.·Front Immunol
2023Review
The syn3 strain HSZP of herpes simplex virus type 1 (HSV-1) is not pathogenic for mice and shows limited neural spread.
Rajcáni J et al.·Virus Res
1996
Identification of novel targets and pathways to distinguish suicide dependent or independent on depression diagnosis.
Peng S et al.·Sci Rep
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Syn3 Gene Knockout Negatively Impacts Aspects of Reversal Learning Performance.
Moore A et al.·eNeuro
2021🔓 Open Access
Intravesical rAd-IFNα/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study.
Shore ND et al.·J Clin Oncol
2017Cohort
Phase 1b Trial to Evaluate Tissue Response to a Second Dose of Intravesical Recombinant Adenoviral Interferon α2b Formulated in Syn3 for Failures of Bacillus Calmette-Guerin (BCG) Therapy in Nonmuscle Invasive Bladder Cancer.
Navai N et al.·Ann Surg Oncol
2016
Use of monitoring levels of soluble forms of cytokeratin 18 in the urine of patients with superficial bladder cancer following intravesical Ad-IFNα/Syn3 treatment in a phase l study.
Benedict WF et al.·Cancer Gene Ther
2014🔓 Open AccessCohort
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Muscle Invasive Bladder Urothelial CarcinomaStage II Bladder Cancer AJCC v8Stage IIIA Bladder Cancer AJCC v8

Neoadjuvant Intravesical Nadofaragene Firadenovec With Gemcitabine, Cisplatin and Durvalumab for the Treatment of Muscle Invasive Bladder Cancer, TRIFECTA Trial

NOT YET RECRUITING
NCT07332351Phase PHASE2University of WashingtonStarted 2026-03-01
Nadofaragene FiradenovecDurvalumabGemcitabine

External Resources

Links to major genomics databases and tools