F2 (Prothrombin) variants and mutations
F2 (also known as Prothrombin) is a human protein-coding gene encoding a prothrombin protein. After cleavage to thrombin, it converts fibrinogen to fibrin and activates multiple additional coagulation components to amplify clot formation. Deficiency can cause bleeding, whereas the common G20210A variant raises prothrombin levels and increases venous-thrombosis risk. This analysis covers 874 F2 variants and mutations. Of these, 78% have computational variant effect predictions. Disease context includes congenital prothrombin deficiency, Congenital factor II deficiency, and thrombophilia due to thrombin defect. Example F2 variants include M1L, M1I, and A2T.
Variant analysis overview
- Gene: F2
- Protein: Prothrombin
- UniProt accession: P00734
- Organism: Homo sapiens
- Variants analyzed: 874
- Variant scope: all variants
- Completed: 2026-09-09
Variant and mutation evidence
- Variant composition: 676 unspecified-consequence records; 65 synonymous variants; 146 missense variants; 11 frameshift variants; 17 stop-gained variants; 3 in-frame insertions; 3 splice-region variants; 2 in-frame deletions; 14 substitution
- Prediction scores: 681 variants have prediction scores (78% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: congenital prothrombin deficiency, Congenital factor II deficiency, thrombophilia due to thrombin defect, venous thromboembolism, deep vein thrombosis, blood coagulation disease, ischemic stroke, prothrombin deficiency, pulmonary embolism, hereditary thrombophilia due to congenital protein C deficiency, Thromboembolism, Thrombocytopenia.
Protein structure and variant hotspots
- Protein features: 4 domains; 13 post-translational modification sites.
- Structural context: 572 variants have structural context.
- PTM context: 45 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, ClinGen, MaveDB, LitVar.
Notable F2 variants
Examples include M1L, M1I, A2T, A2V, A2A, A2P, A2S, A2D. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1L (p.Met1Leu), gnomAD 11-46719415-A-C, CADD 5.37
- M1I (p.Met1Ile), gnomAD 11-46719703-G-A, CADD 18.60
- A2T (p.Ala2Thr), cosmic curated COSV61315, gnomAD rs1195889853, REVEL 0.34, CADD 22.60
- A2V (p.Ala2Val), rs775306348, NCI-TCGA Cosmic COSV1003, cosmic curated COSV10031, ExAC rs775306348, REVEL 0.26, CADD 13.90, Variant assessed as somatic; moderate impact.
- A2A (p.Ala2Ala), rs748368751, gnomAD 11-46719241-G-T, CADD 13.50
- A2P (p.Ala2Pro), rs1472234628, gnomAD 11-46719385-G-C, CADD 0.95
- A2S (p.Ala2Ser), gnomAD 11-46719385-G-T, CADD 0.90
- A2D (p.Ala2Asp), rs1156783231, gnomAD 11-46719386-C-A, CADD 2.17
- H3D (p.His3Asp), ExAC rs773112047, gnomAD rs773112047, REVEL 0.43, CADD 22.60
- H3Y (p.His3Tyr), ExAC rs773112047, gnomAD rs773112047, REVEL 0.33, CADD 22.50
- H3H (p.His3His), rs763098369, gnomAD 11-46719244-C-T, CADD 11.90
- V4I (p.Val4Ile), rs766756950, NCI-TCGA Cosmic COSV6131, cosmic curated COSV61317, ExAC rs766756950, REVEL 0.24, CADD 12.40, Variant assessed as somatic; moderate impact.
- V4L (p.Val4Leu), gnomAD 11-46719245-G-C, REVEL 0.23, CADD 14.90
- V4A (p.Val4Ala), gnomAD 11-46719246-T-C, REVEL 0.34, CADD 23.50
- V4V (p.Val4Val), gnomAD 11-46719247-C-A, CADD 12.40
- R5* (p.Arg5Ter), rs775021214, ClinGen CA380260043, ClinVar RCV003627748, CADD 33.00, Pathogenic
- R5G (p.Arg5Gly), rs775021214, NCI-TCGA Cosmic COSV1003, cosmic curated COSV10031, ExAC rs775021214, REVEL 0.23, CADD 18.40, Pathogenic
- R5Q (p.Arg5Gln), Ensembl rs758038546, REVEL 0.56, CADD 22.50
- R5L (p.Arg5Leu), gnomAD 11-46719249-G-T, REVEL 0.32, CADD 22.80
- R5R (p.Arg5Arg), gnomAD 11-46719250-A-C, CADD 9.14
- G6V (p.Gly6Val), gnomAD 11-46719252-G-T, REVEL 0.53, CADD 25.30
- G6A (p.Gly6Ala), gnomAD 11-46719371-G-C, CADD 6.41
- G6G (p.Gly6Gly), rs1200098359, gnomAD 11-46719372-C-T, CADD 4.40
- G6R (p.Gly6Arg), rs1360389263, gnomAD 11-46719388-G-A, CADD 0.47
- L7F (p.Leu7Phe), gnomAD 11-46719253-C-CT, CADD 24.00
- L7L (p.Leu7Leu), rs1389698444, gnomAD 11-46719254-T-C, CADD 12.60
- L7W (p.Leu7Trp), gnomAD 11-46719255-T-G, REVEL 0.42, CADD 23.50
- L7S (p.Leu7Ser), gnomAD 11-46719255-T-C, REVEL 0.56, CADD 16.50
- L7P (p.Leu7Pro), gnomAD 11-46719377-GTC-G, CADD 6.03
- L7I (p.Leu7Ile), gnomAD 11-46719379-C-A, CADD 7.63
- L7M (p.Leu7Met), gnomAD 11-46719382-C-A, CADD 4.17
- Q8E (p.Gln8Glu), gnomAD rs1421101265
- Q8A (p.Gln8Ala), gnomAD 11-46719255-T-TG, CADD 23.00
- Q8H (p.Gln8His), gnomAD 11-46719259-G-T, REVEL 0.24, CADD 15.30
- Q8K (p.Gln8Lys), gnomAD 11-46719400-C-A, CADD 4.30
- Q8P (p.Gln8Pro), gnomAD 11-46719401-A-C, CADD 4.57
- Q8Q (p.Gln8Gln), gnomAD 11-46719402-G-A, CADD 6.75
- L9M (p.Leu9Met), gnomAD rs1385031430, REVEL 0.29, CADD 20.30
- P10L (p.Pro10Leu), ExAC rs767987956, TOPMed rs767987956, gnomAD rs767987956, REVEL 0.25, CADD 14.80
- P10S (p.Pro10Ser), ExAC rs760170533, TOPMed rs760170533, gnomAD rs760170533, REVEL 0.22, CADD 10.10
- P10A (p.Pro10Ala), gnomAD 11-46719263-C-G, REVEL 0.23, CADD 7.25
- P10T (p.Pro10Thr), gnomAD 11-46719263-C-A, REVEL 0.27, CADD 8.75
- P10P (p.Pro10Pro), gnomAD 11-46719265-T-C, CADD 7.93
- P10H (p.Pro10His), gnomAD 11-46719410-C-A, CADD 5.08
- P10R (p.Pro10Arg), gnomAD 11-46719410-C-G, CADD 5.28
- G11V (p.Gly11Val), Ensembl rs1245607845
- G11D (p.Gly11Asp), gnomAD 11-46719267-G-A, REVEL 0.60, CADD 23.30
- C12R (p.Cys12Arg), ExAC rs753169407, gnomAD rs753169407, REVEL 0.63, CADD 25.20
- L13L (p.Leu13Leu), rs1294754974, gnomAD 11-46719272-C-T, CADD 11.50
- L13P (p.Leu13Pro), gnomAD 11-46719273-T-C, REVEL 0.72, CADD 26.80
- A14V (p.Ala14Val), Ensembl rs2064820021
- A14T (p.Ala14Thr), gnomAD 11-46719275-G-A, REVEL 0.28, CADD 19.20
- A14A (p.Ala14Ala), gnomAD 11-46719277-C-A, CADD 12.20
- L15A (p.Leu15Ala), gnomAD 11-46719275-G-GCT, CADD 24.50
- L15I (p.Leu15Ile), rs958872946, gnomAD 11-46719412-C-A, CADD 4.34
- L15L (p.Leu15Leu), rs1309051707, gnomAD 11-46719414-A-G, CADD 3.85
- A17S (p.Ala17Ser), TOPMed rs1394538588, gnomAD rs1394538588, REVEL 0.30, CADD 7.42, Uncertain significance, Pregnancy loss, recurrent, susceptibility to, 2; Ischemic stroke; Congenital pro
- A17V (p.Ala17Val), ExAC rs763811997, TOPMed rs763811997, gnomAD rs763811997, REVEL 0.25, CADD 7.27
- A17P (p.Ala17Pro), gnomAD 11-46719284-G-C, REVEL 0.57, CADD 12.60
- A17G (p.Ala17Gly), gnomAD 11-46719285-C-G, REVEL 0.30, CADD 8.93
- A17A (p.Ala17Ala), gnomAD 11-46719286-C-G, CADD 11.80
- L18R (p.Leu18Arg), gnomAD rs1454798621, REVEL 0.66, CADD 23.50
- L18L (p.Leu18Leu), gnomAD 11-46719287-C-T, CADD 9.81
- C19Y (p.Cys19Tyr), Ensembl rs1198351107
- C19A (p.Cys19Ala), NCI-TCGA Cosmic COSV6131, cosmic curated COSV61317, Variant assessed as somatic; moderate impact.
- C19W (p.Cys19Trp), gnomAD 11-46719292-T-G, REVEL 0.37, CADD 11.00
- C19C (p.Cys19Cys), rs2064820205, gnomAD 11-46719292-T-C, CADD 7.67
- S20S (p.Ser20Ser), rs1456728300, gnomAD 11-46719295-C-T, CADD 12.00
- S20R (p.Ser20Arg), gnomAD 11-46719394-A-C, CADD 7.31
- S20C (p.Ser20Cys), gnomAD 11-46719394-A-T, CADD 7.18
- S20T (p.Ser20Thr), rs1035565130, gnomAD 11-46719395-G-C, CADD 5.36
- S20N (p.Ser20Asn), rs1035565130, gnomAD 11-46719395-G-A, CADD 5.77
- S20I (p.Ser20Ile), gnomAD 11-46719404-G-T, CADD 6.43
- H23Q (p.His23Gln), TOPMed rs1207410654, gnomAD rs1207410654, REVEL 0.33, CADD 14.50, Likely benign
- S24G (p.Ser24Gly), gnomAD rs1269394557, REVEL 0.34, CADD 16.00
- S24R (p.Ser24Arg), gnomAD rs1464830560, REVEL 0.48, CADD 22.30
- Q25R (p.Gln25Arg), ExAC rs753243533, gnomAD rs753243533
- Q25* (p.Gln25Ter), gnomAD 11-46719308-C-T, CADD 36.00
- H26P (p.His26Pro), TOPMed rs2064820305
- V27L (p.Val27Leu), gnomAD 11-46719314-G-T, REVEL 0.78, CADD 35.00
- V27A (p.Val27Ala), gnomAD 11-46719702-T-C, REVEL 0.76, CADD 29.10
- F28V (p.Phe28Val), TOPMed rs2064822800
- F28F (p.Phe28Phe), gnomAD 11-46719706-C-T, CADD 16.10
- F28L (p.Phe28Leu), gnomAD 11-46719706-C-A, REVEL 0.81, CADD 26.30
- L29W (p.Leu29Trp), rs2064822815, gnomAD 11-46719705-TC-T, CADD 26.30
- L29L (p.Leu29Leu), rs1168671118, gnomAD 11-46719707-C-T, CADD 15.70
- L29P (p.Leu29Pro), gnomAD 11-46719708-T-C, REVEL 0.89, CADD 28.90
- A30P (p.Ala30Pro), gnomAD rs1389231675, REVEL 0.48, CADD 23.00
- A30T (p.Ala30Thr), gnomAD rs1389231675, REVEL 0.35, CADD 21.80
- A30S (p.Ala30Ser), gnomAD 11-46719710-G-T, REVEL 0.33, CADD 23.00
- A30G (p.Ala30Gly), gnomAD 11-46719711-C-G, REVEL 0.25, CADD 15.60
- A30V (p.Ala30Val), gnomAD 11-46719711-C-T, REVEL 0.25, CADD 17.70
- A30D (p.Ala30Asp), gnomAD 11-46719711-C-A, REVEL 0.25, CADD 13.50
- P31A (p.Pro31Ala), TOPMed rs1427401369, gnomAD rs1427401369
- P31S (p.Pro31Ser), TOPMed rs1427401369, gnomAD rs1427401369, REVEL 0.27, CADD 14.80
- P31T (p.Pro31Thr), gnomAD 11-46719713-C-A, REVEL 0.30, CADD 21.30
- P31L (p.Pro31Leu), gnomAD 11-46719714-C-T, REVEL 0.31, CADD 21.10
- P31H (p.Pro31His), gnomAD 11-46719714-C-A, REVEL 0.27, CADD 16.30
- Q32E (p.Gln32Glu), cosmic curated COSV99043, TOPMed rs1167405248, gnomAD rs1167405248, REVEL 0.28, CADD 15.80
- Q32K (p.Gln32Lys), gnomAD 11-46719716-C-A, REVEL 0.28, CADD 16.60
- Q32* (p.Gln32Ter), gnomAD 11-46719716-C-T, CADD 35.00
- Q32R (p.Gln32Arg), gnomAD 11-46719717-A-G, REVEL 0.21, CADD 20.70
- Q32L (p.Gln32Leu), gnomAD 11-46719717-A-T, REVEL 0.36, CADD 23.50
- Q32H (p.Gln32His), gnomAD 11-46719718-G-T, REVEL 0.42, CADD 22.30
- Q32Q (p.Gln32Gln), rs1457865248, gnomAD 11-46719718-G-A, CADD 11.20
- Q33* (p.Gln33Ter), gnomAD rs1292220529
- Q33P (p.Gln33Pro), rs1234951610, ClinGen CA380260354, ClinVar RCV000994613, TOPMed rs1234951610, REVEL 0.53, CADD 23.20, Uncertain significance, not provided
- p.Gln33 Ser36del, rs769517071, gnomAD 11-46719717-AGCAA, CADD 22.40
- Q33K (p.Gln33Lys), gnomAD 11-46719719-C-A, REVEL 0.30, CADD 21.30
- Q33R (p.Gln33Arg), gnomAD 11-46719720-A-G, REVEL 0.18, CADD 19.80
- Q33Q (p.Gln33Gln), gnomAD 11-46719721-A-G, CADD 16.10
- A34T (p.Ala34Thr), Ensembl rs1335354324, REVEL 0.77, CADD 28.70
- p.Ala34 Arg35insLeuPheLeuAlaProG, rs755345665, gnomAD 11-46719314-G-GTG, CADD 20.90
- A34S (p.Ala34Ser), gnomAD 11-46719722-G-T, REVEL 0.77, CADD 27.40
- A34E (p.Ala34Glu), gnomAD 11-46719723-C-A, REVEL 0.81, CADD 25.90
- A34V (p.Ala34Val), gnomAD 11-46719723-C-T, REVEL 0.77, CADD 26.30
- A34A (p.Ala34Ala), rs1592407655, gnomAD 11-46719724-A-G, CADD 5.39
- R35G (p.Arg35Gly), rs144785536, NCI-TCGA Cosmic COSV6131, cosmic curated COSV61314, 1000Genomes rs144785536, REVEL 0.27, CADD 14.70, Uncertain significance
- R35L (p.Arg35Leu), TOPMed rs1296934945, gnomAD rs1296934945, REVEL 0.27, CADD 10.20, Uncertain significance
- R35Q (p.Arg35Gln), rs1296934945, cosmic curated COSV10966, TOPMed rs1296934945, gnomAD rs1296934945, REVEL 0.21, CADD 14.90, Uncertain significance, Inborn genetic diseases
- R35W (p.Arg35Trp), rs144785536, ClinGen CA5966808, cosmic curated COSV10031, NCI-TCGA Cosmic COSV6131, REVEL 0.31, CADD 16.40, Uncertain significance, Inborn genetic diseases; not provided
- R35R (p.Arg35Arg), rs144785536, gnomAD 11-46719725-C-A, CADD 9.25
- S36L (p.Ser36Leu), ExAC rs764885504, TOPMed rs764885504, gnomAD rs764885504, REVEL 0.49, CADD 23.90
- S36P (p.Ser36Pro), gnomAD 11-46719728-T-C, REVEL 0.59, CADD 24.40
- S36* (p.Ser36Ter), gnomAD 11-46719729-C-A, CADD 34.00
- S36S (p.Ser36Ser), rs148596790, gnomAD 11-46719730-G-A, CADD 11.70
- L37Q (p.Leu37Gln), Ensembl rs894338780, REVEL 0.72, CADD 28.20
- L37V (p.Leu37Val), rs755345665, gnomAD 11-46719314-G-GTG, CADD 27.60
- L37L (p.Leu37Leu), gnomAD 11-46719731-C-T, CADD 12.30
- L37M (p.Leu37Met), gnomAD 11-46719731-C-A, REVEL 0.31, CADD 17.50
- L37P (p.Leu37Pro), gnomAD 11-46719732-T-C, REVEL 0.78, CADD 29.20
- L38V (p.Leu38Val), rs755345665, gnomAD 11-46719314-G-GTG, CADD 27.50
- L38I (p.Leu38Ile), gnomAD 11-46719734-C-A, REVEL 0.59, CADD 24.70
- L38P (p.Leu38Pro), gnomAD 11-46719735-T-C, REVEL 0.91, CADD 29.70
- L38L (p.Leu38Leu), gnomAD 11-46719736-C-A, CADD 9.27
- p.Gln39 Arg40insLeuPheLeuAlaProG, rs755345665, gnomAD 11-46719314-G-GTG, CADD 20.40
- Q39H (p.Gln39His), gnomAD 11-46719314-G-GTG, CADD 27.30
- Q39* (p.Gln39Ter), gnomAD 11-46719737-C-T, CADD 34.00
- Q39R (p.Gln39Arg), gnomAD 11-46719738-A-G, REVEL 0.23, CADD 11.00
- R40Q (p.Arg40Gln), ExAC rs762485669, TOPMed rs762485669, gnomAD rs762485669, REVEL 0.87, CADD 32.00, Uncertain significance, not specified
- R40W (p.Arg40Trp), rs1013222460, ClinGen CA221647167, ClinVar RCV003147152, ClinVar RCV003992747, REVEL 0.85, CADD 26.50, Conflicting interpretations, not provided; Congenital prothrombin deficiency
- R40R (p.Arg40Arg), gnomAD 11-46719740-C-A, CADD 12.70
- R40L (p.Arg40Leu), gnomAD 11-46719741-G-T, REVEL 0.85, CADD 28.70
- p.Val41 Arg42insLeuPheLeuAlaProG, rs755345665, gnomAD 11-46719314-G-GTG, CADD 20.20
- V41S (p.Val41Ser), gnomAD 11-46719740-CG-C, CADD 27.90
- V41F (p.Val41Phe), gnomAD 11-46719743-G-T, REVEL 0.35, CADD 14.50
- V41I (p.Val41Ile), gnomAD 11-46719743-G-A, REVEL 0.21, CADD 13.60
- V41V (p.Val41Val), gnomAD 11-46719745-C-T, CADD 6.69
- R42Q (p.Arg42Gln), gnomAD rs1263681706, REVEL 0.69, CADD 24.80
- R42W (p.Arg42Trp), rs2502815919, ClinGen CA380260400, ClinVar RCV003516328, REVEL 0.85, CADD 26.20, Conflicting interpretations, Congenital prothrombin deficiency
- R42R (p.Arg42Arg), gnomAD 11-46719746-C-A, CADD 10.80
- R42L (p.Arg42Leu), gnomAD 11-46719747-G-T, REVEL 0.73, CADD 24.60
- R43* (p.Arg43Ter), cosmic curated COSV10885, ExAC rs766255526, gnomAD rs766255526, CADD 31.00
- R43Q (p.Arg43Gln), TOPMed rs1565700695, REVEL 0.79, CADD 25.50
- R43R (p.Arg43Arg), gnomAD 11-46719749-C-A, CADD 6.74
- R43G (p.Arg43Gly), gnomAD 11-46719749-C-G, REVEL 0.78, CADD 22.10
- A44S (p.Ala44Ser), gnomAD 11-46719752-G-T, REVEL 0.70, CADD 23.30
- A44V (p.Ala44Val), gnomAD 11-46719753-C-T, REVEL 0.78, CADD 24.40
- A44D (p.Ala44Asp), gnomAD 11-46719753-C-A, REVEL 0.79, CADD 24.40
- A44A (p.Ala44Ala), gnomAD 11-46719754-C-A, CADD 9.27
- N45N (p.Asn45Asn), rs946360744, gnomAD 11-46719757-C-T, CADD 8.20
- T46A (p.Thr46Ala), Ensembl rs2134523337, REVEL 0.43, CADD 18.10
- T46I (p.Thr46Ile), cosmic curated COSV10814, ExAC rs751494277, gnomAD rs751494277, REVEL 0.46, CADD 14.80
- T46N (p.Thr46Asn), ExAC rs751494277, gnomAD rs751494277, REVEL 0.40, CADD 8.42
- T46P (p.Thr46Pro), rs1478737126, gnomAD 11-46719397-A-C, CADD 6.18
- T46T (p.Thr46Thr), rs2064821022, gnomAD 11-46719399-A-T, CADD 3.13
- T46S (p.Thr46Ser), gnomAD 11-46719759-C-G, REVEL 0.39, CADD 1.95
- F47L (p.Phe47Leu), gnomAD 11-46719763-C-G, REVEL 0.41, CADD 11.30
- F47F (p.Phe47Phe), gnomAD 11-46719763-C-T, CADD 7.50
- L48F (p.Leu48Phe), gnomAD 11-46719766-G-T, REVEL 0.53, CADD 14.50
- E49D (p.Glu49Asp), TOPMed rs1447320783, gnomAD rs1447320783, REVEL 0.75, CADD 23.90
- E49K (p.Glu49Lys), ExAC rs754914460, gnomAD rs754914460
- E49Q (p.Glu49Gln), ExAC rs754914460, gnomAD rs754914460, REVEL 0.84, CADD 26.20
- E49* (p.Glu49Ter), gnomAD 11-46719767-G-T, CADD 36.00
- E50K (p.Glu50Lys), gnomAD 11-46719770-G-A, REVEL 0.92, CADD 25.90
- E50G (p.Glu50Gly), gnomAD 11-46719771-A-G, REVEL 0.94, CADD 27.90
- E50D (p.Glu50Asp), gnomAD 11-46719772-G-T, REVEL 0.77, CADD 22.90
- V51G (p.Val51Gly), Ensembl rs1592407741
- V51L (p.Val51Leu), gnomAD rs1183194405, REVEL 0.34, CADD 0.00
- V51M (p.Val51Met), gnomAD rs1183194405, REVEL 0.35, CADD 0.00
Public F2 analysis runs
- F2 analysis run — F2 (874 variants) — completed 2026-09-09
- F2 analysis run — F2 (934 variants) — completed 2026-08-10