NOS3

Chr 7AR

nitric oxide synthase 3

Also known as: ECNOS, MYMY8, eNOS

NCBI Gene: 4846ENSG00000164867UniProt: P60323

Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. Nitric oxide is synthesized from L-arginine by nitric oxide synthases. Variations in this gene are associated with susceptibility to coronary spasm. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]

Primary Disease Associations & Inheritance

Moyamoya disease 8MIM #621469
AR
352
ClinVar variants
77
Pathogenic / LP
0.00
pLI score
6
Active trials
Clinical Summary— NOS3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
77 Pathogenic / Likely Pathogenic· 174 VUS of 352 total submissions
💊
Clinical Trials
6 active or recruiting trials — 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.
0.50LOEUF
pLI 0.000
Z-score 4.82
OE 0.35 (0.25–0.50)
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.
2.04Z-score
OE missense 0.79 (0.74–0.85)
610 obs / 768.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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 (0.25–0.50)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.79 (0.74–0.85)
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.0.96
0≤1.21.6
LoF obs/exp: 23 / 65.0Missense obs/exp: 610 / 768.9Syn Z: 0.50

ClinVar Variant Classifications

352 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic71
Likely Pathogenic6
VUS174
Likely Benign48
Benign52
Conflicting1
71
Pathogenic
6
Likely Pathogenic
174
VUS
48
Likely Benign
52
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
71
0
71
Likely Pathogenic
0
2
4
0
6
VUS
2
161
11
0
174
Likely Benign
0
11
11
26
48
Benign
0
10
31
11
52
Conflicting
—1
Total218412837352

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

View in ClinVar →

Protein Context — Lollipop Plot

NOS3 · 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

Moyamoya disease 8

MIM #621469

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Stroke genetics informs drug discovery and risk prediction across ancestries.
Mishra A et al.·Nature
2022Meta-analysis
Genome-Wide CRISPR/Cas9 Library Screening Identified that DUSP4 Deficiency Induces Lenvatinib Resistance in Hepatocellular Carcinoma.
Huang S et al.·Int J Biol Sci
2022
Endothelial nitric oxide synthase: From biochemistry and gene structure to clinical implications of NOS3 polymorphisms.
Oliveira-Paula GH et al.·Gene
2016Review
2'-5' oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability.
Kim TK et al.·Nat Commun
2022
Fenofibrate and metabolic syndrome.
Kraja AT et al.·Endocr Metab Immune Disord Drug Targets
2010Review
Interaction between caffeine consumption & genetic susceptibility in Parkinson's disease: A systematic review.
Yang Y et al.·Ageing Res Rev
2024Review
Germline DNA Damage Repair Gene Alterations in Patients with Metachronous Breast and Colorectal Cancer.
Villacis RAR et al.·Int J Mol Sci
2024Cohort
Pharmacogenomics for the treatment of dementia.
Cacabelos R·Ann Med
2002Review
Endothelial nitric oxide synthase in the microcirculation.
Shu X et al.·Cell Mol Life Sci
2015Review
Nitric oxide and intestinal inflammation.
Kubes P et al.·Am J Med
2000Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
CubeSat cybersecurity dataset for intrusion detection (CuCD-ID): Labelled NOS3/cFS telemetry (raw + augmented) with COSMOS reproduction scripts.
Fayyaz Y et al.·Data Brief
2026🔓 Open Access
Circulating Extracellular Vesicles Downregulate NOS3 Expression in Endothelial Cells in Atrial Fibrillation.
Leimon N et al.·J Clin Med
2026
ETS Homologous Factor Drives Endothelial Dysfunction in Diabetes-Related Erectile Dysfunction via Regulating SPRY1 Ubiquitination and NOS3 Autophagy.
Liu C et al.·World J Mens Health
2026
T-786C Polymorphism of the NOS3 Gene and Its Role in the Development of Renal Dysfunction in Patients of the Uzbek Population with Chronic Heart Failure.
Zakirova G et al.·Turk Kardiyol Dern Ars
2026Cohort
Association of MMP9 and NOS3 Polymorphisms with Distinct Clinical Forms of Juvenile Scleroderma and Characteristics of Humoral Immunity.
Osminina M et al.·Int J Mol Sci
2026🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Fabry DiseaseEndothelial DysfunctionMicrovasculature

Characterizing the Retinal Microvasculature in Patients with Fabry Disease: a Prospective Observational Study

RECRUITING
NCT06758648Technical University of MunichStarted 2020-06-25
Dynamic retinal vessel analysis (DVA)Biochemistry and immune phenotypingQuestionnaires (Patient reported outcomes)
Cerebral Aneurysm

Effect of Sirolimus on Molecular Alterations in Cerebral Aneurysms

RECRUITING
NCT04141020Phase PHASE2University of MiamiStarted 2021-10-27
Microsurgical clippingEndovascular treatmentSirolimus
Coronary Artery Disease

Prediction of Atherosclerotic Plaque Progression

ACTIVE NOT RECRUITING
NCT05424705Na Homolce HospitalStarted 2015-01-15
OCT, NIRS
Cancer

Onco Move - Improvement of Psychophysical Fitness in Adult Cancer Survivors

NOT YET RECRUITING
NCT07087652Phase NAGdansk University of Physical Education and SportStarted 2025-09-01
Onco Move multicomponent face-to-face training program
Anterior Wall Myocardial Infarction

The Enhanced Angiogenic Cell Therapy - Acute Myocardial Infarction Trial

ACTIVE NOT RECRUITING
NCT00936819Phase PHASE2Ottawa Hospital Research InstituteStarted 2013-07-19
Plasma-Lyte A and 25% Autologous PlasmaAutologous EPCsAutologous EPCs Transfected with human eNOS
Exercise TrainingGenetic Polymorphism

Effects of Exercise Training and Genetic Factors in Hypertensive Patients with Obstructive Sleep Apnea Sleep

ENROLLING BY INVITATION
NCT06687863Phase NAUniversity of Sao Paulo General HospitalStarted 2024-02-26
Exercise training

External Resources

Links to major genomics databases and tools