CASP8 (Caspase-8) variants and mutations
CASP8 (also known as Caspase-8) is a human protein-coding gene encoding a caspase-8 protein. It initiates death-receptor-mediated apoptosis but also regulates lymphocyte activation and inflammatory signaling. Biallelic loss-of-function variants can cause immunodeficiency with defective apoptosis and lymphocyte homeostasis, while somatic pathway alterations can promote cancer-cell survival. This analysis covers 1,585 CASP8 variants and mutations. Of these, 40% have computational variant effect predictions. Disease context includes autoimmune lymphoproliferative syndrome type 2B, Autoimmune lymphoproliferative syndrome with recurrent viral infections, and head and neck squamous cell carcinoma. Example CASP8 variants include M1?, D2H, and F3C.
Variant analysis overview
- Gene: CASP8
- Protein: Caspase-8
- UniProt accession: Q14790
- Organism: Homo sapiens
- Variants analyzed: 1585
- Variant scope: all variants
- Completed: 2026-08-22
Variant and mutation evidence
- Variant composition: 1,379 unspecified-consequence records; 1 stop-gained variants; 109 missense variants; 72 synonymous variants; 24 frameshift variants; 3 splice-region variants; 2 in-frame deletions
- Prediction scores: 640 variants have prediction scores (40% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: autoimmune lymphoproliferative syndrome type 2B, Autoimmune lymphoproliferative syndrome with recurrent viral infections, head and neck squamous cell carcinoma, neurodegenerative disease, viral infectious disease, autoimmune lymphoproliferative syndrome, ovarian carcinoma, basal cell carcinoma, prostate carcinoma, hepatocellular carcinoma, breast cancer, nasopharyngeal neoplasm.
Protein structure and variant hotspots
- Protein features: 2 domains; 7 post-translational modification sites.
- Structural context: 524 variants have structural context.
- PTM context: 20 variants overlap post-translational modification sites.
Data sources
Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable CASP8 variants
Examples include M1?, D2H, F3C, F3L, F3V, S4I, S4T, S4R. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1?, cosmic curated COSV10634, cosmic curated COSV10508, cosmic curated COSV51847, cosmic curated COSV99965, Variant assessed as somatic; high impact.
- D2H (p.Asp2His), cosmic curated COSV10957, Ensembl rs2125152889
- F3C (p.Phe3Cys), cosmic curated COSV51847, gnomAD rs1264556426, CADD 23.90, PolyPhen-2 0.96
- F3L (p.Phe3Leu), cosmic curated COSV51854
- F3V (p.Phe3Val), gnomAD 2-201266493-T-G, CADD 23.30, PolyPhen-2 0.54
- S4I (p.Ser4Ile), cosmic curated COSV10940, TOPMed rs1456626812, gnomAD rs1456626812, CADD 0.19, PolyPhen-2 0.05
- S4T (p.Ser4Thr), gnomAD 2-201266497-G-C, CADD 0.03, PolyPhen-2 0.00
- S4R (p.Ser4Arg), gnomAD 2-201266498-C-G, CADD 0.19, PolyPhen-2 0.00
- S4S (p.Ser4Ser), gnomAD 2-201266498-C-T, CADD 2.23
- R5G (p.Arg5Gly), NCI-TCGA Cosmic COSV5185, cosmic curated COSV51851, Variant assessed as somatic; moderate impact.
- R5I (p.Arg5Ile), NCI-TCGA Cosmic COSV5184, cosmic curated COSV51844, Variant assessed as somatic; moderate impact.
- R5T (p.Arg5Thr), Ensembl rs2125152947
- R5K (p.Arg5Lys), rs2125045953, gnomAD 2-201258245-G-A, CADD 4.05
- R5R (p.Arg5Arg), gnomAD 2-201258246-A-G, CADD 2.12
- N6T (p.Asn6Thr), gnomAD 2-201258275-GA-G, CADD 0.48
- N6H (p.Asn6His), gnomAD 2-201258277-A-C, CADD 12.00
- L7F (p.Leu7Phe), cosmic curated COSV10508, NCI-TCGA Cosmic COSV5184, CADD 23.20, PolyPhen-2 0.99, Variant assessed as somatic; moderate impact.
- L7H (p.Leu7His), cosmic curated COSV51850
- L7R (p.Leu7Arg), NCI-TCGA Cosmic COSV5185, NCI-TCGA Cosmic COSV9996, cosmic curated COSV99965, Variant assessed as somatic; moderate impact.
- L7V (p.Leu7Val), NCI-TCGA Cosmic COSV5184, cosmic curated COSV51847, Ensembl rs2125152960, Variant assessed as somatic; moderate impact.
- L7L (p.Leu7Leu), rs1206946200, gnomAD 2-201266507-T-C, CADD 0.81
- Y8* (p.Tyr8Ter), NCI-TCGA Cosmic COSV5185, cosmic curated COSV51851, Variant assessed as somatic; high impact.
- Y8C (p.Tyr8Cys), rs895052255, ClinGen CA63878502, ClinVar RCV001997201, TOPMed rs895052255, CADD 17.90, PolyPhen-2 0.84, Uncertain significance, Autoimmune lymphoproliferative syndrome type 2B
- Y8S (p.Tyr8Ser), TOPMed rs895052255, gnomAD rs895052255, CADD 16.30, PolyPhen-2 0.04, Uncertain significance
- D9G (p.Asp9Gly), rs1270676492, ClinGen CA350281189, ClinVar RCV001960144, gnomAD rs1270676492, CADD 6.37, PolyPhen-2 0.01, Uncertain significance, Autoimmune lymphoproliferative syndrome type 2B
- D9N (p.Asp9Asn), rs747412250, ClinGen CA2053437, cosmic curated COSV99964, ClinVar RCV002604543, CADD 0.27, PolyPhen-2 0.01, Uncertain significance, Autoimmune lymphoproliferative syndrome type 2B
- I10F (p.Ile10Phe), cosmic curated COSV10457, NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- I10T (p.Ile10Thr), NCI-TCGA Cosmic COSV5185, cosmic curated COSV51852, CADD 24.10, PolyPhen-2 1.00, Variant assessed as somatic; moderate impact.
- I10L (p.Ile10Leu), gnomAD 2-201258261-TA-T, CADD 15.50
- I10M (p.Ile10Met), gnomAD 2-201258262-AT-A, CADD 8.32
- I10S (p.Ile10Ser), gnomAD 2-201258263-T-G, CADD 5.00
- G11E (p.Gly11Glu), NCI-TCGA Cosmic COSV5185, cosmic curated COSV51856, Variant assessed as somatic; moderate impact.
- G11R (p.Gly11Arg), NCI-TCGA Cosmic COSV5185, cosmic curated COSV51853, Variant assessed as somatic; moderate impact.
- G11V (p.Gly11Val), Ensembl rs2125153068
- G11G (p.Gly11Gly), gnomAD 2-201258240-A-T, CADD 4.10
- G11D (p.Gly11Asp), rs1947123947, gnomAD 2-201258242-G-A, CADD 9.54
- G11T (p.Gly11Thr), rs777586802, gnomAD 2-201258276-A-AAA, CADD 15.10
- G11A (p.Gly11Ala), gnomAD 2-201258290-G-C, CADD 2.48
- G11Q (p.Gly11Gln), rs1947134021, gnomAD 2-201258329-TAG-T, CADD 22.30
- G11S (p.Gly11Ser), gnomAD 2-201258331-G-A, CADD 18.80
- G11C (p.Gly11Cys), gnomAD 2-201258373-G-T, CADD 16.20
- E12G (p.Glu12Gly), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- E12K (p.Glu12Lys), cosmic curated COSV99044, CADD 18.50
- E12* (p.Glu12Ter), rs868455063, gnomAD 2-201258235-G-T, CADD 32.00
- E12V (p.Glu12Val), rs200010059, gnomAD 2-201258236-A-T, CADD 0.50
- E12Q (p.Glu12Gln), rs377242086, gnomAD 2-201258265-G-C, CADD 16.20
- E12D (p.Glu12Asp), gnomAD 2-201266520-GA-G, CADD 24.80
- Q13K (p.Gln13Lys), Ensembl rs2125153103
- Q13R (p.Gln13Arg), gnomAD 2-201266524-A-G, CADD 10.30, PolyPhen-2 0.01
- L14P (p.Leu14Pro), cosmic curated COSV10585
- L14Q (p.Leu14Gln), gnomAD 2-201266527-T-A, CADD 24.30, PolyPhen-2 1.00
- L14L (p.Leu14Leu), rs755684176, gnomAD 2-201266528-G-A, CADD 2.98
- D15E (p.Asp15Glu), Ensembl rs2125153163
- D15H (p.Asp15His), Ensembl rs1947837560, Uncertain significance
- D15N (p.Asp15Asn), rs1947837560, ClinGen CA350281315, ClinVar RCV001230579, NCI-TCGA TCGA novel, CADD 14.80, PolyPhen-2 0.26, Uncertain significance, Autoimmune lymphoproliferative syndrome type 2B
- D15G (p.Asp15Gly), gnomAD 2-201266530-A-G, CADD 0.04, PolyPhen-2 0.04
- S16N (p.Ser16Asn), Ensembl rs2125153188
- S16R (p.Ser16Arg), rs1401364865, ClinGen CA350281341, ClinVar RCV001953058, TOPMed rs1401364865, CADD 7.95, PolyPhen-2 0.46, Uncertain significance, Autoimmune lymphoproliferative syndrome type 2B
- S16V (p.Ser16Val), gnomAD 2-201258265-GA-G, CADD 21.80
- S16T (p.Ser16Thr), rs1219836548, gnomAD 2-201258269-G-C, CADD 21.50
- S16S (p.Ser16Ser), gnomAD 2-201258270-T-C, CADD 8.68
- S16G (p.Ser16Gly), gnomAD 2-201266532-A-G, CADD 16.10, PolyPhen-2 0.61
- E17G (p.Glu17Gly), TOPMed rs1947838015
- E17Q (p.Glu17Gln), Ensembl rs2125153224
- E17E (p.Glu17Glu), gnomAD 2-201266537-A-G, CADD 0.14
- D18H (p.Asp18His), cosmic curated COSV51857
- D18N (p.Asp18Asn), NCI-TCGA Cosmic COSV5184, NCI-TCGA Cosmic COSV5185, Uncertain significance, Inborn genetic diseases; Autoimmune lymphoproliferative syndrome type 2B
- D18V (p.Asp18Val), cosmic curated COSV51854
- D18Y (p.Asp18Tyr), NCI-TCGA Cosmic COSV5184, cosmic curated COSV51847, NCI-TCGA Cosmic COSV5185, Variant assessed as somatic; moderate impact.
- L19P (p.Leu19Pro), TOPMed rs1477942244, gnomAD rs1477942244, CADD 25.40
- L19V (p.Leu19Val), gnomAD 2-201258286-C-G, CADD 7.09
- A20V (p.Ala20Val), Ensembl rs2125153296
- A20G (p.Ala20Gly), rs762986379, gnomAD 2-201258251-C-G, CADD 14.30
- A20D (p.Ala20Asp), rs1489060781, gnomAD 2-201258293-C-A, CADD 15.10
- A20A (p.Ala20Ala), rs1009720305, gnomAD 2-201258294-C-T, CADD 3.87
- A20C (p.Ala20Cys), gnomAD 2-201258311-C-CT, CADD 13.40
- A20P (p.Ala20Pro), gnomAD 2-201258313-G-C, CADD 0.07
- A20S (p.Ala20Ser), gnomAD 2-201266544-G-T, CADD 22.10, PolyPhen-2 0.93
- S21C (p.Ser21Cys), gnomAD rs1182373153, CADD 23.90, PolyPhen-2 0.84
- S21F (p.Ser21Phe), cosmic curated COSV51850
- S21S (p.Ser21Ser), gnomAD 2-201266549-C-T, CADD 8.42
- L22F (p.Leu22Phe), NCI-TCGA Cosmic COSV9996, cosmic curated COSV99965, Ensembl rs2125153336, Variant assessed as somatic; moderate impact.
- L22I (p.Leu22Ile), cosmic curated COSV99965
- K23E (p.Lys23Glu), cosmic curated COSV51854
- K23R (p.Lys23Arg), rs779778498, ClinGen CA2053439, ClinVar RCV003067178, ClinVar RCV005535506, CADD 26.10, PolyPhen-2 0.94, Uncertain significance, Inborn genetic diseases; Autoimmune lymphoproliferative syndrome type 2B
- K23I (p.Lys23Ile), rs3769823, gnomAD 2-201258272-A-T, CADD 22.20
- K23K (p.Lys23Lys), gnomAD 2-201266555-G-A, CADD 5.23
- F24C (p.Phe24Cys), TOPMed rs1947838842
- F24L (p.Phe24Leu), NCI-TCGA TCGA novel, NCI-TCGA Cosmic COSV9996, cosmic curated COSV99965, Ensembl rs2125153376, Variant assessed as somatic; moderate impact.
- F24I (p.Phe24Ile), rs1286373288, gnomAD 2-201258295-T-A, CADD 5.29
- F24F (p.Phe24Phe), rs748514005, gnomAD 2-201258309-C-T, CADD 3.90
- L25P (p.Leu25Pro), NCI-TCGA Cosmic COSV5185, cosmic curated COSV51854, Variant assessed as somatic; moderate impact.
- L25L (p.Leu25Leu), rs748943405, gnomAD 2-201266561-G-A, CADD 4.26
- S26C (p.Ser26Cys), gnomAD 2-201258339-AGGGG, CADD 22.70
- S26Y (p.Ser26Tyr), rs749203863, gnomAD 2-201258346-TCGGA, CADD 21.10
- S26A (p.Ser26Ala), gnomAD 2-201258346-T-G, CADD 6.37
- S26L (p.Ser26Leu), rs767472565, gnomAD 2-201258347-C-T, CADD 8.12
- S26S (p.Ser26Ser), rs370221663, gnomAD 2-201258348-G-A, CADD 3.26
- S26N (p.Ser26Asn), gnomAD 2-201266563-G-A, CADD 22.60, PolyPhen-2 0.90
- S26R (p.Ser26Arg), gnomAD 2-201266564-C-A, CADD 20.50, PolyPhen-2 0.93
- L27M (p.Leu27Met), NCI-TCGA Cosmic COSV9996, cosmic curated COSV99965, Variant assessed as somatic; moderate impact.
- L27Q (p.Leu27Gln), ExAC rs768253756, gnomAD rs768253756, CADD 21.20, PolyPhen-2 0.31
- L27V (p.Leu27Val), gnomAD 2-201258325-GAGTT, CADD 21.80
- L27S (p.Leu27Ser), rs1185530380, gnomAD 2-201258329-T-C, CADD 4.09
- L27L (p.Leu27Leu), gnomAD 2-201266567-G-A, CADD 5.98
- D28G (p.Asp28Gly), cosmic curated COSV51845, Ensembl rs966912274
- D28V (p.Asp28Val), Ensembl rs966912274
- D28Y (p.Asp28Tyr), NCI-TCGA Cosmic COSV5185, cosmic curated COSV51854, Ensembl rs2125153432, Variant assessed as somatic; moderate impact.
- D28D (p.Asp28Asp), rs368413113, gnomAD 2-201266570-C-T, CADD 0.74
- Y29C (p.Tyr29Cys), gnomAD rs1430228154, CADD 10.30, PolyPhen-2 0.01
- Y29D (p.Tyr29Asp), cosmic curated COSV51849
- Y29H (p.Tyr29His), gnomAD 2-201266571-T-C, CADD 0.00, PolyPhen-2 0.00
- Y29Y (p.Tyr29Tyr), rs774076043, gnomAD 2-201266573-C-T, CADD 1.27
- I30I (p.Ile30Ile), rs1468329326, gnomAD 2-201266576-T-A, CADD 0.54
- P31A (p.Pro31Ala), TOPMed rs1559350009, Uncertain significance
- P31L (p.Pro31Leu), rs748087575, ClinGen CA2053443, NCI-TCGA Cosmic COSV5184, cosmic curated COSV51847, CADD 20.00, PolyPhen-2 0.97, Uncertain significance, Autoimmune lymphoproliferative syndrome type 2B
- P31S (p.Pro31Ser), rs1559350009, ClinGen CA350282389, ClinVar RCV001895790, TOPMed rs1559350009, CADD 17.60, PolyPhen-2 0.74, Uncertain significance, Autoimmune lymphoproliferative syndrome type 2B
- P31T (p.Pro31Thr), gnomAD 2-201258298-C-A, CADD 19.70
- P31P (p.Pro31Pro), gnomAD 2-201258300-C-G, CADD 1.47
- P31H (p.Pro31His), rs34210251, gnomAD 2-201258305-C-A, CADD 16.50
- P31R (p.Pro31Arg), rs34210251, gnomAD 2-201258305-C-G, CADD 16.10
- P31Q (p.Pro31Gln), gnomAD 2-201266578-C-A, CADD 18.90, PolyPhen-2 0.99
- Q32* (p.Gln32Ter), cosmic curated COSV51861
- Q32E (p.Gln32Glu), rs999368756, ClinGen CA63878565, ClinVar RCV001248049, TOPMed rs999368756, CADD 6.57, PolyPhen-2 0.22, Uncertain significance, Autoimmune lymphoproliferative syndrome type 2B
- R33K (p.Arg33Lys), Ensembl rs2125153637
- R33S (p.Arg33Ser), rs138862018, ClinGen CA2053445, ClinVar RCV002979704, ESP rs138862018, CADD 20.90, PolyPhen-2 0.16, Uncertain significance, Autoimmune lymphoproliferative syndrome type 2B
- R33R (p.Arg33Arg), rs2125047617, gnomAD 2-201258336-G-A, CADD 2.49
- K34T (p.Lys34Thr), gnomAD 2-201266587-A-C, CADD 25.20, PolyPhen-2 0.98
- K34K (p.Lys34Lys), rs760545881, gnomAD 2-201266588-G-A, CADD 8.49
- Q35* (p.Gln35Ter), TOPMed rs1344190376, gnomAD rs1344190376
- Q35E (p.Gln35Glu), TOPMed rs1344190376, gnomAD rs1344190376
- Q35K (p.Gln35Lys), TOPMed rs1344190376, gnomAD rs1344190376, CADD 22.90, PolyPhen-2 0.30
- Q35L (p.Gln35Leu), gnomAD rs1402540575, CADD 17.10, PolyPhen-2 0.04
- E36* (p.Glu36Ter), NCI-TCGA Cosmic COSV5184, cosmic curated COSV51848, Variant assessed as somatic; high impact.
- E36D (p.Glu36Asp), cosmic curated COSV10585
- E36G (p.Glu36Gly), Ensembl rs2125153787
- E36K (p.Glu36Lys), NCI-TCGA Cosmic COSV5184, Ensembl rs2125153761, Variant assessed as somatic; moderate impact.
- E36E (p.Glu36Glu), rs1947133169, gnomAD 2-201258327-G-A, CADD 2.59
- E36R (p.Glu36Arg), rs1432940998, gnomAD 2-201258347-CG-C, CADD 2.37
- P37S (p.Pro37Ser), Ensembl rs2125153804
- P37T (p.Pro37Thr), rs1947138527, gnomAD 2-201258364-C-A, CADD 19.10
- P37Q (p.Pro37Gln), rs753962983, gnomAD 2-201258365-C-A, CADD 13.30
- P37P (p.Pro37Pro), rs920682794, gnomAD 2-201258366-A-G, CADD 8.37
- I38F (p.Ile38Phe), cosmic curated COSV99966
- I38M (p.Ile38Met), NCI-TCGA Cosmic COSV9996, cosmic curated COSV99965, Variant assessed as somatic; moderate impact.
- I38N (p.Ile38Asn), cosmic curated COSV99966
- I38T (p.Ile38Thr), NCI-TCGA Cosmic COSV9996, CADD 25.90, PolyPhen-2 0.84, Variant assessed as somatic; moderate impact.
- I38V (p.Ile38Val), rs771007977, ClinGen CA2053447, ClinVar RCV002640550, ClinVar RCV005537538, CADD 20.90, PolyPhen-2 0.56, Uncertain significance, Autoimmune lymphoproliferative syndrome type 2B; Inborn genetic diseases
- I38L (p.Ile38Leu), gnomAD 2-201266466-A-C, CADD 0.06
- I38I (p.Ile38Ile), rs776887648, gnomAD 2-201266600-C-T, CADD 10.60
- K39N (p.Lys39Asn), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- K39E (p.Lys39Glu), gnomAD 2-201266601-A-G, CADD 3.37, PolyPhen-2 0.03
- K39M (p.Lys39Met), gnomAD 2-201266602-A-T, CADD 22.80, PolyPhen-2 0.87
- D40E (p.Asp40Glu), rs759793127, cosmic curated COSV99964, ClinGen CA2053449, ClinVar RCV001334877, CADD 13.30, PolyPhen-2 0.60, Uncertain significance, Autoimmune lymphoproliferative syndrome type 2B
- D40H (p.Asp40His), Ensembl rs2125153868
- D40N (p.Asp40Asn), Ensembl rs2125153868
- D40V (p.Asp40Val), gnomAD 2-201266605-A-T, CADD 25.70, PolyPhen-2 0.96
- A41D (p.Ala41Asp), cosmic curated COSV51851, CADD 24.00, PolyPhen-2 0.98
- A41G (p.Ala41Gly), TOPMed rs1356214774, CADD 22.60, PolyPhen-2 0.56
- A41S (p.Ala41Ser), cosmic curated COSV99964
- A41V (p.Ala41Val), TOPMed rs1356214774, CADD 22.80, PolyPhen-2 0.66
- A41A (p.Ala41Ala), gnomAD 2-201258357-G-A, CADD 9.67
- A41T (p.Ala41Thr), rs879524077, gnomAD 2-201258379-G-A, CADD 10.70
- A41E (p.Ala41Glu), rs373349998, gnomAD 2-201258380-C-A, CADD 13.80
- A41P (p.Ala41Pro), gnomAD 2-201266607-G-C, CADD 13.80, PolyPhen-2 0.31
- L42* (p.Leu42Ter), cosmic curated COSV99044
- L42L (p.Leu42Leu), rs1270927174, gnomAD 2-201258339-A-G, CADD 4.51
- L42E (p.Leu42Glu), gnomAD 2-201266607-GCCTT, CADD 28.80
- M43I (p.Met43Ile), Ensembl rs2125153986, CADD 9.40, PolyPhen-2 0.14
- M43V (p.Met43Val), Ensembl rs1947843704, CADD 10.20
- M43T (p.Met43Thr), gnomAD 2-201258359-T-C, CADD 5.44
- M43K (p.Met43Lys), gnomAD 2-201258359-T-A, CADD 7.26
- M43L (p.Met43Leu), gnomAD 2-201266613-A-T, CADD 15.00, PolyPhen-2 0.10
- L44I (p.Leu44Ile), Ensembl rs2125154004
- L44L (p.Leu44Leu), gnomAD 2-201266616-T-C, CADD 6.42
- L44S (p.Leu44Ser), gnomAD 2-201266617-T-C, CADD 25.70, PolyPhen-2 0.99
- F45L (p.Phe45Leu), Ensembl rs2125154024
- Q46H (p.Gln46His), ExAC rs752831902, TOPMed rs752831902, gnomAD rs752831902, CADD 23.30, PolyPhen-2 0.86
- R47G (p.Arg47Gly), cosmic curated COSV51848
- R47K (p.Arg47Lys), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
Public CASP8 analysis runs
- CASP8 analysis run — CASP8 (1,585 variants) — completed 2026-08-22