NOS3 (Nitric oxide synthase 3) variants and mutations
NOS3 (also known as Nitric oxide synthase 3) is a human protein-coding gene encoding a nitric oxide synthase 3 protein. It generates nitric oxide in vascular endothelium, promoting smooth-muscle relaxation, inhibiting platelet activation, and supporting vascular homeostasis. Reduced activity contributes to endothelial dysfunction, while common genetic variation has modest effects on cardiovascular traits. This analysis covers 1,667 NOS3 variants and mutations. Of these, 76% have computational variant effect predictions. Disease context includes hypertensive disorder, essential hypertension, and myocardial infarction. Example NOS3 variants include G2D, G2A, and G2G.
Variant analysis overview
- Gene: NOS3
- Protein: Nitric oxide synthase 3
- UniProt accession: P29474
- Organism: Homo sapiens
- Variants analyzed: 1667
- Variant scope: all variants
- Completed: 2026-08-21
Variant and mutation evidence
- Variant composition: 1,454 unspecified-consequence records; 109 missense variants; 76 synonymous variants; 19 frameshift variants; 5 in-frame deletions; 3 stop-gained variants; 3 splice-region variants; 1 substitution
- Prediction scores: 1,274 variants have prediction scores (76% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: hypertensive disorder, essential hypertension, myocardial infarction, coronary artery disorder, stroke disorder, heart disorder, myocardial ischemia, primary ovarian failure, cardiovascular disorder, neurodegenerative disease, acute myocardial infarction, coronary atherosclerosis.
Protein structure and variant hotspots
- Protein features: 2 domains; 42 binding sites; 10 post-translational modification sites.
- Structural context: 489 variants have structural context.
- PTM context: 12 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable NOS3 variants
Examples include G2D, G2A, G2G, N3N, L4F, K5N, K5R, K5K. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- G2D (p.Gly2Asp), gnomAD 7-150993808-G-A, REVEL 0.17, CADD 26.10
- G2A (p.Gly2Ala), gnomAD 7-150993808-G-C, REVEL 0.12, CADD 25.50
- G2G (p.Gly2Gly), gnomAD 7-150993809-C-A, CADD 11.30
- N3N (p.Asn3Asn), rs754037991, gnomAD 7-150993812-C-T, CADD 10.50
- L4F (p.Leu4Phe), gnomAD 7-150993815-G-T, REVEL 0.05, CADD 23.90
- K5N (p.Lys5Asn), rs1363067747, NCI-TCGA Cosmic COSV5249, cosmic curated COSV52493, TOPMed rs1363067747, REVEL 0.10, CADD 24.40, Variant assessed as somatic; moderate impact.
- K5R (p.Lys5Arg), gnomAD rs1164406674, REVEL 0.08, CADD 24.60
- K5K (p.Lys5Lys), gnomAD 7-150993818-G-A, CADD 10.10
- S6T (p.Ser6Thr), rs1312281138, NCI-TCGA Cosmic COSV9987, cosmic curated COSV99871, TOPMed rs1312281138, REVEL 0.14, CADD 22.40, Variant assessed as somatic; moderate impact.
- S6R (p.Ser6Arg), gnomAD 7-150993820-GC-G, CADD 15.10
- S6S (p.Ser6Ser), rs759850942, gnomAD 7-150993821-C-T, CADD 5.00
- V7M (p.Val7Met), 1000Genomes rs147771478, ESP rs147771478, ExAC rs147771478, TOPMed rs147771478, REVEL 0.14, CADD 24.40, Uncertain significance, not specified
- p.Val7 Pro14del, gnomAD 7-150993820-GCGTG, CADD 17.40
- V7L (p.Val7Leu), gnomAD 7-150993822-G-T, REVEL 0.11, CADD 22.90
- V7E (p.Val7Glu), gnomAD 7-150993823-T-A, REVEL 0.19, CADD 25.30
- A8P (p.Ala8Pro), gnomAD 7-150993823-TGG-T, CADD 24.80
- A8S (p.Ala8Ser), gnomAD 7-150993825-G-T, REVEL 0.04, CADD 18.40
- A8T (p.Ala8Thr), gnomAD 7-150993825-G-A, REVEL 0.06, CADD 19.80
- A8D (p.Ala8Asp), gnomAD 7-150993826-C-A, REVEL 0.07, CADD 20.30
- A8A (p.Ala8Ala), gnomAD 7-150993827-C-A, CADD 7.88
- Q9R (p.Gln9Arg), gnomAD rs1201953550, REVEL 0.12, CADD 22.90
- p.Gln9 Glu10del, rs2117095233, gnomAD 7-150993826-CCCAG, CADD 14.20
- Q9H (p.Gln9His), gnomAD 7-150993830-G-T, REVEL 0.14, CADD 22.30
- E10D (p.Glu10Asp), cosmic curated COSV52496, 1000Genomes rs2117095251, REVEL 0.05, CADD 5.74
- E10K (p.Glu10Lys), rs547845670, NCI-TCGA Cosmic COSV5248, cosmic curated COSV52488, NCI-TCGA Cosmic COSV5249, REVEL 0.06, CADD 22.20, Variant assessed as somatic; moderate impact.
- E10A (p.Glu10Ala), gnomAD 7-150993832-A-C, REVEL 0.07, CADD 21.00
- P11S (p.Pro11Ser), ESP rs141170595, ExAC rs141170595, TOPMed rs141170595, gnomAD rs141170595, REVEL 0.11, CADD 6.41
- P11T (p.Pro11Thr), cosmic curated COSV10512, ESP rs141170595, ExAC rs141170595, TOPMed rs141170595, REVEL 0.13, CADD 11.30, Benign, not provided
- P11A (p.Pro11Ala), gnomAD 7-150993834-C-G, REVEL 0.07, CADD 10.50
- P11L (p.Pro11Leu), gnomAD 7-150993835-C-T, REVEL 0.08, CADD 20.70
- P11R (p.Pro11Arg), gnomAD 7-150993835-C-G, REVEL 0.07, CADD 19.60
- P11P (p.Pro11Pro), gnomAD 7-150993836-T-C, CADD 0.79
- G12E (p.Gly12Glu), rs757589399, ClinGen CA4566460, ClinVar RCV004488200, ExAC rs757589399, REVEL 0.09, CADD 20.70, Uncertain significance, not specified
- G12V (p.Gly12Val), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- G12G (p.Gly12Gly), gnomAD 7-150993839-G-A, CADD 6.89
- P13L (p.Pro13Leu), ESP rs201968188, ExAC rs201968188, TOPMed rs201968188, gnomAD rs201968188, REVEL 0.11, CADD 21.50
- P13S (p.Pro13Ser), TOPMed rs925565610, gnomAD rs925565610, REVEL 0.09, CADD 23.20
- P14L (p.Pro14Leu), NCI-TCGA Cosmic COSV5248, cosmic curated COSV52489, Variant assessed as somatic; moderate impact.
- P14P (p.Pro14Pro), gnomAD 7-150993845-C-G, CADD 3.09
- C15F (p.Cys15Phe), ExAC rs755834879, TOPMed rs755834879, gnomAD rs755834879, REVEL 0.18, CADD 23.00
- C15R (p.Cys15Arg), ExAC rs745489730, gnomAD rs745489730, REVEL 0.20, CADD 20.90
- C15W (p.Cys15Trp), 1000Genomes rs779537885, ExAC rs779537885, TOPMed rs779537885, gnomAD rs779537885, REVEL 0.24, CADD 2.53
- C15Y (p.Cys15Tyr), ExAC rs755834879, TOPMed rs755834879, gnomAD rs755834879, REVEL 0.14, CADD 23.00
- C15C (p.Cys15Cys), rs779537885, gnomAD 7-150993848-C-T, CADD 0.18
- G16S (p.Gly16Ser), cosmic curated COSV99871, 1000Genomes rs368332097, ESP rs368332097, ExAC rs368332097, REVEL 0.18, CADD 22.90
- G16C (p.Gly16Cys), gnomAD 7-150993849-G-T, REVEL 0.21, CADD 23.20
- G16G (p.Gly16Gly), rs1359834869, gnomAD 7-150993851-C-T, CADD 6.83
- L17P (p.Leu17Pro), gnomAD 7-150993853-T-C, REVEL 0.15, CADD 22.70
- G18E (p.Gly18Glu), TOPMed rs1802308138
- G18R (p.Gly18Arg), gnomAD 7-150993855-G-A, REVEL 0.12, CADD 22.90
- G18G (p.Gly18Gly), gnomAD 7-150993857-G-A, CADD 4.01
- L19R (p.Leu19Arg), TOPMed rs1802308218
- L19L (p.Leu19Leu), rs1802308303, gnomAD 7-150993860-G-A, CADD 6.62
- G20R (p.Gly20Arg), cosmic curated COSV10512, TOPMed rs1178452647, REVEL 0.15, CADD 25.40
- p.Gly20 Leu25del, gnomAD 7-150993854-GGGGC, CADD 17.70
- G20E (p.Gly20Glu), gnomAD 7-150993862-G-A, REVEL 0.16, CADD 24.40
- G20V (p.Gly20Val), gnomAD 7-150993862-G-T, REVEL 0.17, CADD 24.40
- G20A (p.Gly20Ala), gnomAD 7-150993862-G-C, REVEL 0.09, CADD 22.80
- L21P (p.Leu21Pro), gnomAD 7-150993865-T-C, REVEL 0.10, CADD 24.00
- G22S (p.Gly22Ser), TOPMed rs1563206770, REVEL 0.18, CADD 22.40
- G22D (p.Gly22Asp), gnomAD 7-150993868-G-A, REVEL 0.23, CADD 22.60
- G22G (p.Gly22Gly), rs1405675455, gnomAD 7-150993869-C-T, CADD 7.71
- L23P (p.Leu23Pro), gnomAD 7-150993871-T-C, REVEL 0.13, CADD 23.80
- p.Gly24 Leu25del, gnomAD 7-150993851-CCTGG, CADD 15.60
- L25L (p.Leu25Leu), rs768525535, gnomAD 7-150993878-G-T, CADD 2.51
- C26Y (p.Cys26Tyr), gnomAD 7-150993880-G-A, REVEL 0.16, CADD 22.10
- C26C (p.Cys26Cys), rs199642317, gnomAD 7-150993881-C-T, CADD 4.78
- G27C (p.Gly27Cys), 1000Genomes rs372106353, ESP rs372106353, ExAC rs372106353, gnomAD rs372106353
- G27D (p.Gly27Asp), ExAC rs771786669, gnomAD rs771786669, REVEL 0.04, CADD 21.70
- G27S (p.Gly27Ser), cosmic curated COSV52489, 1000Genomes rs372106353, ESP rs372106353, ExAC rs372106353, REVEL 0.04, CADD 14.10
- G27R (p.Gly27Arg), gnomAD 7-150993882-G-C, REVEL 0.09, CADD 18.50
- K28Q (p.Lys28Gln), gnomAD rs1294845766
- p.Lys28 Gly30delinsAsn, rs1331591723, gnomAD 7-150993886-AGCAG, CADD 16.50
- K28K (p.Lys28Lys), rs1802308988, gnomAD 7-150993887-G-A, CADD 7.66
- Q29E (p.Gln29Glu), gnomAD 7-150993888-C-G, REVEL 0.06, CADD 15.90
- Q29Q (p.Gln29Gln), gnomAD 7-150993890-G-A, CADD 7.78
- G30D (p.Gly30Asp), rs773099942, ExAC rs773099942, gnomAD rs773099942, REVEL 0.08, CADD 16.30, Variant assessed as somatic; moderate impact.
- G30V (p.Gly30Val), gnomAD 7-150993892-G-T, REVEL 0.05, CADD 15.90
- G30G (p.Gly30Gly), gnomAD 7-150993893-C-A, CADD 8.63
- P31S (p.Pro31Ser), TOPMed rs1451795121, gnomAD rs1451795121, REVEL 0.09, CADD 16.90
- P31P (p.Pro31Pro), rs976977218, gnomAD 7-150993896-A-C, CADD 4.74
- A32D (p.Ala32Asp), ExAC rs759672158, gnomAD rs759672158, REVEL 0.09, CADD 16.10
- T33I (p.Thr33Ile), ExAC rs765551784, gnomAD rs765551784, REVEL 0.08, CADD 10.20
- P34A (p.Pro34Ala), TOPMed rs913170985, REVEL 0.11, CADD 14.30
- P34L (p.Pro34Leu), rs556096751, 1000Genomes rs556096751, ExAC rs556096751, gnomAD rs556096751, REVEL 0.07, CADD 19.70, Uncertain significance, not specified
- P34Q (p.Pro34Gln), gnomAD 7-150993904-C-A, REVEL 0.07, CADD 18.60
- P34R (p.Pro34Arg), gnomAD 7-150993904-C-G, REVEL 0.06, CADD 22.30
- P34P (p.Pro34Pro), rs763127838, gnomAD 7-150993905-G-A, CADD 0.28
- A35G (p.Ala35Gly), gnomAD 7-150993900-A-AC, CADD 22.50
- A35T (p.Ala35Thr), gnomAD 7-150993906-G-A, REVEL 0.02, CADD 6.37
- A35D (p.Ala35Asp), gnomAD 7-150993907-C-A, REVEL 0.02, CADD 10.70
- P36S (p.Pro36Ser), gnomAD 7-150993909-C-T, REVEL 0.03, CADD 0.17
- E37G (p.Glu37Gly), gnomAD rs1484645038, REVEL 0.17, CADD 22.90
- E37* (p.Glu37Ter), gnomAD 7-150993912-G-T, CADD 36.00
- E37D (p.Glu37Asp), gnomAD 7-150993914-G-T, REVEL 0.09, CADD 14.00
- P38R (p.Pro38Arg), TOPMed rs907719973, gnomAD rs907719973, REVEL 0.07, CADD 15.20, Uncertain significance, not specified
- P38P (p.Pro38Pro), gnomAD 7-150993917-C-A, CADD 6.70
- S39G (p.Ser39Gly), gnomAD 7-150993918-A-G, REVEL 0.05, CADD 13.40
- S39I (p.Ser39Ile), gnomAD 7-150993919-G-T, REVEL 0.03, CADD 13.40
- S39S (p.Ser39Ser), rs1317395596, gnomAD 7-150993920-C-T, CADD 4.58
- R40G (p.Arg40Gly), ExAC rs764652925, TOPMed rs764652925, gnomAD rs764652925, REVEL 0.05, CADD 6.27
- R40Q (p.Arg40Gln), 1000Genomes rs199688227, ESP rs199688227, ExAC rs199688227, TOPMed rs199688227, REVEL 0.02, CADD 0.33, Likely benign, not specified
- R40W (p.Arg40Trp), rs764652925, cosmic curated COSV10462, NCI-TCGA Cosmic COSV9987, ExAC rs764652925, REVEL 0.08, CADD 11.50, Uncertain significance, not specified
- R40R (p.Arg40Arg), gnomAD 7-150993921-C-A, CADD 4.46
- R40L (p.Arg40Leu), gnomAD 7-150993922-G-T, REVEL 0.04, CADD 1.08
- A41D (p.Ala41Asp), TOPMed rs867562196, gnomAD rs867562196, REVEL 0.09, CADD 7.64
- A41S (p.Ala41Ser), rs1802310466, ClinGen CA369851011, ClinVar RCV004488191, gnomAD rs1802310466, REVEL 0.04, CADD 5.89, Uncertain significance, not specified
- A41T (p.Ala41Thr), gnomAD 7-150993924-G-A, REVEL 0.04, CADD 9.33
- A41A (p.Ala41Ala), gnomAD 7-150993926-C-A, CADD 0.99
- P42L (p.Pro42Leu), gnomAD 7-150993928-C-T, REVEL 0.14, CADD 23.10
- P42P (p.Pro42Pro), rs1429050496, gnomAD 7-150993929-A-G, CADD 0.35
- A43S (p.Ala43Ser), gnomAD 7-150993930-G-T, REVEL 0.01, CADD 4.70
- A43T (p.Ala43Thr), gnomAD 7-150993930-G-A, REVEL 0.01, CADD 7.57
- A43E (p.Ala43Glu), gnomAD 7-150993931-C-A, REVEL 0.03, CADD 4.66
- S44I (p.Ser44Ile), gnomAD 7-150993931-C-CA, CADD 20.40
- S44P (p.Ser44Pro), gnomAD 7-150993933-T-C, REVEL 0.03, CADD 11.20
- S44F (p.Ser44Phe), gnomAD 7-150993934-C-T, REVEL 0.07, CADD 17.50
- S44S (p.Ser44Ser), gnomAD 7-150993935-C-A, CADD 0.51
- L45I (p.Leu45Ile), gnomAD 7-150993936-C-A, REVEL 0.02, CADD 7.08
- L45L (p.Leu45Leu), rs369900681, gnomAD 7-150993938-A-G, CADD 0.17
- L46R (p.Leu46Arg), TOPMed rs996081462, gnomAD rs996081462, REVEL 0.06, CADD 8.83, Uncertain significance, not specified
- L46V (p.Leu46Val), gnomAD 7-150993939-C-G, REVEL 0.02, CADD 1.57
- L46F (p.Leu46Phe), gnomAD 7-150993939-C-T, REVEL 0.03, CADD 4.97
- L46I (p.Leu46Ile), gnomAD 7-150993939-C-A, REVEL 0.03, CADD 2.29
- L46P (p.Leu46Pro), gnomAD 7-150993940-T-C, REVEL 0.09, CADD 12.00
- L46L (p.Leu46Leu), gnomAD 7-150993941-C-A, CADD 1.44
- P47Q (p.Pro47Gln), gnomAD rs866430608, REVEL 0.02, CADD 11.40
- P47T (p.Pro47Thr), gnomAD 7-150993942-C-A, REVEL 0.03, CADD 15.10
- P47L (p.Pro47Leu), gnomAD 7-150993943-C-T, REVEL 0.04, CADD 12.90
- P47P (p.Pro47Pro), gnomAD 7-150993944-A-C, CADD 2.60
- P48A (p.Pro48Ala), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- P48L (p.Pro48Leu), gnomAD rs1453213012, REVEL 0.03, CADD 15.40
- P48S (p.Pro48Ser), ExAC rs750868781, TOPMed rs750868781, gnomAD rs750868781, REVEL 0.03, CADD 16.70
- P48T (p.Pro48Thr), gnomAD 7-150993945-C-A, REVEL 0.03, CADD 15.80
- P48Q (p.Pro48Gln), gnomAD 7-150993946-C-A, REVEL 0.03, CADD 17.10
- P48P (p.Pro48Pro), gnomAD 7-150993947-A-T, CADD 0.76
- A49E (p.Ala49Glu), ExAC rs755710890, TOPMed rs755710890, gnomAD rs755710890, REVEL 0.04, CADD 14.30, Uncertain significance
- A49P (p.Ala49Pro), gnomAD rs1294157279, REVEL 0.05, CADD 15.50
- A49V (p.Ala49Val), rs755710890, ClinGen CA4566481, ClinVar RCV004345066, ExAC rs755710890, REVEL 0.05, CADD 16.10, Uncertain significance, not specified
- A49T (p.Ala49Thr), gnomAD 7-150993948-G-A, REVEL 0.06, CADD 15.10
- A49A (p.Ala49Ala), gnomAD 7-150993950-G-T, CADD 3.78
- P50T (p.Pro50Thr), gnomAD 7-150993951-C-A, REVEL 0.04, CADD 14.90
- P50S (p.Pro50Ser), gnomAD 7-150993951-C-T, REVEL 0.03, CADD 13.70
- P50Q (p.Pro50Gln), gnomAD 7-150993952-C-A, REVEL 0.07, CADD 19.70
- P50P (p.Pro50Pro), rs1301155363, gnomAD 7-150993953-A-C, CADD 9.13
- E51* (p.Glu51Ter), gnomAD rs1344640868, CADD 36.00
- E51K (p.Glu51Lys), gnomAD rs1344640868, REVEL 0.10, CADD 19.20
- E51Q (p.Glu51Gln), gnomAD 7-150993954-G-C, REVEL 0.08, CADD 18.00
- H52Y (p.His52Tyr), gnomAD 7-150993957-C-T, REVEL 0.06, CADD 12.60
- H52R (p.His52Arg), gnomAD 7-150993958-A-G, REVEL 0.08, CADD 5.17
- H52Q (p.His52Gln), gnomAD 7-150993959-C-A, REVEL 0.13, CADD 17.80
- H52H (p.His52His), gnomAD 7-150993959-C-T, CADD 21.90
- S53I (p.Ser53Ile), NCI-TCGA Cosmic COSV9987, cosmic curated COSV99872, REVEL 0.14, CADD 32.00, Variant assessed as somatic; moderate impact.
- S53R (p.Ser53Arg), ExAC rs756506565, gnomAD rs756506565, REVEL 0.12, CADD 17.20
- S53G (p.Ser53Gly), gnomAD 7-150993960-A-G, REVEL 0.11, CADD 24.20
- S53C (p.Ser53Cys), gnomAD 7-150993960-A-T, REVEL 0.12, CADD 26.90
- S53N (p.Ser53Asn), gnomAD 7-150993961-G-A, REVEL 0.15, CADD 28.40
- S53T (p.Ser53Thr), gnomAD 7-150993961-G-C, REVEL 0.16, CADD 29.40
- S53S (p.Ser53Ser), rs756506565, gnomAD 7-150995203-C-T, CADD 15.00
- P54R (p.Pro54Arg), 1000Genomes rs201405443, REVEL 0.07, CADD 19.20
- P54S (p.Pro54Ser), cosmic curated COSV52496, ExAC rs753511043, gnomAD rs753511043, REVEL 0.06, CADD 18.80
- P54T (p.Pro54Thr), ExAC rs753511043, gnomAD rs753511043, REVEL 0.06, CADD 19.90
- P54H (p.Pro54His), gnomAD 7-150995205-C-A, REVEL 0.08, CADD 22.60
- P55L (p.Pro55Leu), rs374957936, cosmic curated COSV52489, NCI-TCGA Cosmic COSV5249, ESP rs374957936, REVEL 0.08, CADD 18.80, Variant assessed as somatic; moderate impact.
- P55R (p.Pro55Arg), gnomAD 7-150995202-GC-G, CADD 33.00
- P55S (p.Pro55Ser), gnomAD 7-150995207-C-T, REVEL 0.06, CADD 14.40
- P55Q (p.Pro55Gln), gnomAD 7-150995208-C-A, REVEL 0.07, CADD 17.60
- P55P (p.Pro55Pro), rs1184486784, gnomAD 7-150995209-G-A, CADD 8.26
- S56G (p.Ser56Gly), gnomAD rs1207876196, REVEL 0.02, CADD 14.60
- S56E (p.Ser56Glu), rs1323072201, gnomAD 7-150995202-G-GC, CADD 36.00
- S56C (p.Ser56Cys), gnomAD 7-150995210-A-T, REVEL 0.08, CADD 23.10
- S57F (p.Ser57Phe), gnomAD rs1231553866, REVEL 0.04, CADD 22.40
- S57P (p.Ser57Pro), gnomAD rs1802345783, REVEL 0.01, CADD 15.80
- S57S (p.Ser57Ser), gnomAD 7-150995215-C-T, CADD 9.55
- P58L (p.Pro58Leu), ExAC rs769056386, TOPMed rs769056386, gnomAD rs769056386, REVEL 0.01, CADD 16.40
- P58R (p.Pro58Arg), ExAC rs769056386, TOPMed rs769056386, gnomAD rs769056386
- P58S (p.Pro58Ser), rs752309888, ClinGen CA4566506, ClinVar RCV001270207, ExAC rs752309888, REVEL 0.03, CADD 16.30, Likely pathogenic, Premature ovarian failure
- P58A (p.Pro58Ala), gnomAD 7-150995216-C-G, REVEL 0.04, CADD 15.00
- P58P (p.Pro58Pro), rs367984752, gnomAD 7-150995218-G-A, CADD 2.02
- L59V (p.Leu59Val), gnomAD 7-150995219-C-G, REVEL 0.02, CADD 10.70
Public NOS3 analysis runs
- NOS3 analysis run — NOS3 (1,667 variants) — completed 2026-08-21