TNFAIP3 (P21580) variants and mutations
TNFAIP3 (also known as P21580) is a human protein-coding gene encoding a tumor necrosis factor alpha-induced protein 3 protein. Its A20 ubiquitin-editing activity terminates NF-kappaB signaling after inflammatory receptor activation and helps prevent excessive immune responses. Haploinsufficiency causes early-onset autoinflammatory disease, while somatic loss occurs in several lymphoid malignancies. This analysis covers 1,799 TNFAIP3 variants and mutations. Of these, 58% have computational variant effect predictions. Disease context includes autoinflammatory syndrome, familial, Behcet-like 1, autoinflammatory syndrome, familial, Behcet-like, and psoriasis. Example TNFAIP3 variants include A2D, A2G, and A2P.
Variant analysis overview
- Gene: TNFAIP3
- Protein: P21580
- UniProt accession: P21580
- Organism: Homo sapiens
- Variants analyzed: 1799
- Variant scope: all variants
- Completed: 2026-08-18
Variant and mutation evidence
- Variant composition: 1,604 unspecified-consequence records; 98 synonymous variants; 80 missense variants; 8 frameshift variants; 1 in-frame deletions; 5 splice-region variants; 3 substitution
- Prediction scores: 1,052 variants have prediction scores (58% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: autoinflammatory syndrome, familial, Behcet-like 1, autoinflammatory syndrome, familial, Behcet-like, psoriasis, systemic lupus erythematosus, familial Behcet-like autoinflammatory syndrome, diffuse large B-cell lymphoma, rheumatoid arthritis, psoriasis vulgaris, autoimmune lymphoproliferative syndrome, asthma, systemic sclerosis, Eczematoid dermatitis.
Protein structure and variant hotspots
- Protein features: 1 domains; 28 binding sites; 4 post-translational modification sites.
- Structural context: 390 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, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable TNFAIP3 variants
Examples include A2D, A2G, A2P, A2T, A2V, A2A, E3*, E3D. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- A2D (p.Ala2Asp), Ensembl rs2114457171
- A2G (p.Ala2Gly), Ensembl rs2114457171
- A2P (p.Ala2Pro), gnomAD rs1207080521
- A2T (p.Ala2Thr), gnomAD rs1207080521
- A2V (p.Ala2Val), Ensembl rs2114457171, MetaLR 0.04, MetaSVM -1.12
- A2A (p.Ala2Ala), rs1267701615, gnomAD 6-137871233-T-C, CADD 11.20
- E3* (p.Glu3Ter), cosmic curated COSV52798
- E3D (p.Glu3Asp), Ensembl rs2114457248
- E3K (p.Glu3Lys), cosmic curated COSV52798, Ensembl rs2114457225
- E3Q (p.Glu3Gln), Ensembl rs2114457225, MetaLR 0.02, MetaSVM -1.06
- Q4* (p.Gln4Ter), Ensembl rs2114457272
- Q4E (p.Gln4Glu), Ensembl rs2114457272
- Q4H (p.Gln4His), TOPMed rs1776048469, MetaLR 0.01, MetaSVM -1.02
- Q4K (p.Gln4Lys), cosmic curated COSV10510
- Q4L (p.Gln4Leu), Ensembl rs2114457305, MetaLR 0.02, MetaSVM -1.08
- V5D (p.Val5Asp), Ensembl rs2114457362
- V5G (p.Val5Gly), Ensembl rs2114457362
- V5L (p.Val5Leu), Ensembl rs2114457344, MetaLR 0.01, MetaSVM -0.92
- V5V (p.Val5Val), rs2114457376, gnomAD 6-137871242-C-A, CADD 8.04
- L6F (p.Leu6Phe), Ensembl rs2114457420, MetaLR 0.12, MetaSVM -0.98, Uncertain significance
- L6I (p.Leu6Ile), rs2114457420, ClinGen CA365779357, ClinVar RCV001915392, Ensembl rs2114457420, MetaLR 0.05, MetaSVM -1.08, Uncertain significance, not provided
- L6V (p.Leu6Val), Ensembl rs2114457420, MetaLR 0.04, MetaSVM -1.07, Uncertain significance
- P7A (p.Pro7Ala), Ensembl rs2114457475
- P7H (p.Pro7His), Ensembl rs2114457518
- P7L (p.Pro7Leu), Ensembl rs2114457518, MetaLR 0.18, MetaSVM -0.80
- P7R (p.Pro7Arg), Ensembl rs2114457518, NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- P7S (p.Pro7Ser), Ensembl rs2114457475
- P7T (p.Pro7Thr), Ensembl rs2114457475, MetaLR 0.18, MetaSVM -0.80
- Q8* (p.Gln8Ter), rs1461832435, ClinGen CA365779383, cosmic curated COSV52799, ClinVar RCV001329556, AlphaMissense 0.09, MetaLR 0.03, Likely pathogenic
- Q8E (p.Gln8Glu), gnomAD rs1461832435, Likely pathogenic
- Q8H (p.Gln8His), TOPMed rs1212266021, gnomAD rs1212266021
- Q8K (p.Gln8Lys), gnomAD rs1461832435, AlphaMissense 0.09, MetaLR 0.03, Likely pathogenic
- Q8L (p.Gln8Leu), Ensembl rs1582884850, Uncertain significance
- Q8R (p.Gln8Arg), rs1582884850, ClinGen CA365779387, ClinVar RCV000998691, Ensembl rs1582884850, AlphaMissense 0.10, MetaLR 0.01, Uncertain significance, not provided
- Q8P (p.Gln8Pro), gnomAD 6-137871250-A-C, CADD 22.40, PolyPhen-2 0.00
- Q8Q (p.Gln8Gln), rs1212266021, gnomAD 6-137871251-G-A, CADD 10.20
- A9P (p.Ala9Pro), gnomAD rs1235795920
- A9S (p.Ala9Ser), gnomAD rs1235795920, MetaLR 0.03, MetaSVM -1.12
- A9T (p.Ala9Thr), gnomAD rs1235795920, MetaLR 0.04, MetaSVM -1.13
- L10* (p.Leu10Ter), Ensembl rs2114457710
- L10F (p.Leu10Phe), Ensembl rs2114457728, MetaLR 0.11, MetaSVM -0.94
- Y11C (p.Tyr11Cys), Ensembl rs2114457781
- Y11D (p.Tyr11Asp), TOPMed rs900039415
- Y11H (p.Tyr11His), TOPMed rs900039415, MetaLR 0.08, MetaSVM -1.05
- Y11N (p.Tyr11Asn), TOPMed rs900039415, MetaLR 0.08, MetaSVM -1.04
- Y11Y (p.Tyr11Tyr), rs1776049197, gnomAD 6-137871260-T-C, CADD 10.20
- L12F (p.Leu12Phe), rs1178250150, NCI-TCGA Cosmic COSV5279, cosmic curated COSV52797, TOPMed rs1178250150, MetaLR 0.02, MetaSVM -1.08, Uncertain significance, not provided
- L12M (p.Leu12Met), cosmic curated COSV52799, 1000Genomes rs138988092, ExAC rs138988092, TOPMed rs138988092, MetaLR 0.01, MetaSVM -1.02, Likely benign
- L12L (p.Leu12Leu), rs138988092, gnomAD 6-137871261-T-C, CADD 11.00
- S13C (p.Ser13Cys), gnomAD rs1470990172, Uncertain significance
- S13G (p.Ser13Gly), rs1470990172, ClinGen CA365779489, ClinVar RCV003827317, ClinVar RCV004366834, MetaLR 0.11, MetaSVM -0.97, Uncertain significance, Inborn genetic diseases; not provided
- S13I (p.Ser13Ile), Ensembl rs2114457877
- S13N (p.Ser13Asn), Ensembl rs2114457877
- S13R (p.Ser13Arg), Ensembl rs2114457908, MetaLR 0.11, MetaSVM -0.96
- N14K (p.Asn14Lys), Ensembl rs2114457960
- N14S (p.Asn14Ser), Ensembl rs2114457942, MetaLR 0.11, MetaSVM -0.95
- M15I (p.Met15Ile), Ensembl rs2114457994, NCI-TCGA Cosmic COSV5280, cosmic curated COSV52801, Variant assessed as somatic; moderate impact.
- M15K (p.Met15Lys), Ensembl rs2114457974, MetaLR 0.04, MetaSVM -1.12
- M15T (p.Met15Thr), gnomAD 6-137871271-T-C, CADD 23.90, PolyPhen-2 0.35
- R16G (p.Arg16Gly), TOPMed rs1414718116, gnomAD rs1414718116, MetaLR 0.04, MetaSVM -1.14, Uncertain significance
- R16Q (p.Arg16Gln), rs759654484, NCI-TCGA Cosmic COSV9939, cosmic curated COSV99396, ExAC rs759654484, MetaLR 0.02, MetaSVM -1.09, Likely benign, not provided
- R16W (p.Arg16Trp), rs1414718116, ClinGen CA365779594, ClinVar RCV002303311, TOPMed rs1414718116, MetaLR 0.05, MetaSVM -1.13, Uncertain significance, not provided
- R16R (p.Arg16Arg), rs1295337888, gnomAD 6-137871275-G-A, CADD 13.10
- K17E (p.Lys17Glu), gnomAD 6-137871276-A-G, CADD 28.90, PolyPhen-2 1.00
- K17T (p.Lys17Thr), gnomAD 6-137871277-A-C, CADD 27.40, PolyPhen-2 1.00
- K17K (p.Lys17Lys), rs767542968, gnomAD 6-137871278-A-G, CADD 13.10
- A18G (p.Ala18Gly), Ensembl rs2114458120
- A18P (p.Ala18Pro), cosmic curated COSV52798, MetaLR 0.12, MetaSVM -1.00
- V19A (p.Val19Ala), cosmic curated COSV10586
- V19E (p.Val19Glu), Ensembl rs2114458175
- V19L (p.Val19Leu), Ensembl rs1776050169, MetaLR 0.03, MetaSVM -1.09
- V19M (p.Val19Met), Ensembl rs1776050169
- V19V (p.Val19Val), rs2114458191, gnomAD 6-137871284-G-A, CADD 12.90
- K20* (p.Lys20Ter), cosmic curated COSV10510
- K20N (p.Lys20Asn), rs1302093455, ClinGen CA365779730, ClinVar RCV003442597, TOPMed rs1302093455, MetaLR 0.09, MetaSVM -1.08, Uncertain significance
- K20Q (p.Lys20Gln), cosmic curated COSV52797, MetaLR 0.03, MetaSVM -1.08
- K20R (p.Lys20Arg), 1000Genomes rs533720482, ExAC rs533720482, TOPMed rs533720482, gnomAD rs533720482, MetaLR 0.04, MetaSVM -1.11
- I21K (p.Ile21Lys), ESP rs149162594, ExAC rs149162594, TOPMed rs149162594, gnomAD rs149162594, MetaLR 0.11, MetaSVM -0.94, Uncertain significance
- I21T (p.Ile21Thr), rs149162594, ClinGen CA4019339, ClinVar RCV002039513, ClinVar RCV004038859, MetaLR 0.11, MetaSVM -0.94, Uncertain significance, Inborn genetic diseases; not provided
- I21V (p.Ile21Val), ExAC rs760487792, gnomAD rs760487792, MetaLR 0.10, MetaSVM -1.06
- I21L (p.Ile21Leu), gnomAD 6-137871288-A-T, CADD 24.50, PolyPhen-2 0.99
- I21I (p.Ile21Ile), rs183283680, gnomAD 6-137871290-A-T, CADD 6.60
- R22G (p.Arg22Gly), TOPMed rs1170624868
- R22L (p.Arg22Leu), NCI-TCGA Cosmic COSV5279, cosmic curated COSV52799, 1000Genomes rs199876928, MetaLR 0.14, MetaSVM -0.95, Uncertain significance
- R22Q (p.Arg22Gln), rs199876928, ClinGen CA148256917, cosmic curated COSV52799, ClinVar RCV001922792, MetaLR 0.13, MetaSVM -1.05, Uncertain significance, not provided
- R22W (p.Arg22Trp), TOPMed rs1170624868, MetaLR 0.10, MetaSVM -0.88
- R22R (p.Arg22Arg), rs2114458367, gnomAD 6-137871293-G-A, CADD 12.60
- E23D (p.Glu23Asp), TOPMed rs1776051086
- E23K (p.Glu23Lys), Ensembl rs2114458400, MetaLR 0.04, MetaSVM -1.10
- E23Q (p.Glu23Gln), gnomAD 6-137871294-G-C, CADD 22.50, PolyPhen-2 0.07
- R24G (p.Arg24Gly), Ensembl rs2114458449
- R24I (p.Arg24Ile), NCI-TCGA Cosmic COSV9939, cosmic curated COSV99396, Variant assessed as somatic; moderate impact.
- R24K (p.Arg24Lys), Ensembl rs2114458467
- R24T (p.Arg24Thr), gnomAD 6-137871298-G-C, CADD 27.50, PolyPhen-2 0.87
- T25I (p.Thr25Ile), rs757112036, ClinGen CA4019341, cosmic curated COSV10586, ClinVar RCV003107073, MetaLR 0.02, MetaSVM -1.03, Uncertain significance
- T25P (p.Thr25Pro), gnomAD 6-137871300-A-C, CADD 24.30, PolyPhen-2 0.47
- E27D (p.Glu27Asp), ExAC rs778507437, gnomAD rs778507437, MetaLR 0.02, MetaSVM -1.02
- E27Q (p.Glu27Gln), Ensembl rs2114458508, MetaLR 0.03, MetaSVM -1.10
- E27A (p.Glu27Ala), gnomAD 6-137871307-A-C, CADD 22.20, PolyPhen-2 0.00
- D28E (p.Asp28Glu), gnomAD rs1298627749
- D28N (p.Asp28Asn), Ensembl rs2114458547, MetaLR 0.12, MetaSVM -1.07
- D28D (p.Asp28Asp), rs1298627749, gnomAD 6-137871311-C-T, CADD 7.42
- I29F (p.Ile29Phe), ESP rs376163335, ExAC rs376163335, TOPMed rs376163335, gnomAD rs376163335, MetaLR 0.02, MetaSVM -1.07
- I29T (p.Ile29Thr), gnomAD rs1226277551, MetaLR 0.04, MetaSVM -1.08
- I29I (p.Ile29Ile), rs1187264052, gnomAD 6-137871314-T-A, CADD 11.50
- F30C (p.Phe30Cys), cosmic curated COSV52802, MetaLR 0.02, MetaSVM -1.07
- F30L (p.Phe30Leu), rs758096571, ClinGen CA4019344, cosmic curated COSV10458, ClinVar RCV002214408, MetaLR 0.01, MetaSVM -1.01, Uncertain significance, not provided
- K31* (p.Lys31Ter), cosmic curated COSV52799, Ensembl rs2114458743, cosmic curated COSV99397, NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- K31T (p.Lys31Thr), gnomAD rs1221152008, MetaLR 0.04, MetaSVM -1.11
- K31K (p.Lys31Lys), rs779395556, gnomAD 6-137871320-A-G, CADD 9.37
- P32R (p.Pro32Arg), cosmic curated COSV10957, MetaLR 0.08, MetaSVM -1.12
- T33A (p.Thr33Ala), ExAC rs746536779, gnomAD rs746536779, MetaLR 0.01, MetaSVM -1.02, Uncertain significance, not provided
- T33S (p.Thr33Ser), Ensembl rs2114458797, MetaLR 0.01, MetaSVM -0.98
- T33I (p.Thr33Ile), gnomAD 6-137871324-AC-A, CADD 23.60
- G35E (p.Gly35Glu), TOPMed rs1447019862
- G35V (p.Gly35Val), TOPMed rs1447019862
- G35W (p.Gly35Trp), cosmic curated COSV10586, MetaLR 0.13, MetaSVM -0.96
- G35R (p.Gly35Arg), gnomAD 6-137871330-G-A, CADD 25.30, PolyPhen-2 0.98
- G35G (p.Gly35Gly), rs1027610200, gnomAD 6-137871332-G-A, CADD 11.60
- I36F (p.Ile36Phe), ExAC rs770145346, gnomAD rs770145346, AlphaMissense 0.29, MetaLR 0.05
- I36L (p.Ile36Leu), rs770145346, ClinGen CA365780128, ClinVar RCV003695341, AlphaMissense 0.29, MetaLR 0.05, Uncertain significance, not provided
- I36M (p.Ile36Met), gnomAD rs1254511072, MetaLR 0.05, MetaSVM -1.14
- I36I (p.Ile36Ile), rs1254511072, gnomAD 6-137871335-C-T, CADD 12.50
- I37S (p.Ile37Ser), NCI-TCGA Cosmic COSV9939, cosmic curated COSV99396, MetaLR 0.11, MetaSVM -0.95, Variant assessed as somatic; moderate impact.
- I37T (p.Ile37Thr), gnomAD 6-137871337-T-C, CADD 27.60, PolyPhen-2 0.99
- H38R (p.His38Arg), cosmic curated COSV52801, MetaLR 0.06, MetaSVM -1.10
- H38Y (p.His38Tyr), Ensembl rs2114458898, MetaLR 0.01, MetaSVM -1.02
- H39Q (p.His39Gln), NCI-TCGA TCGA novel, MetaLR 0.06, MetaSVM -1.07, Variant assessed as somatic; moderate impact.
- H39Y (p.His39Tyr), ExAC rs778400121, gnomAD rs778400121, MetaLR 0.08, MetaSVM -1.09
- H39R (p.His39Arg), gnomAD 6-137871343-A-G, CADD 26.20, PolyPhen-2 1.00
- F40C (p.Phe40Cys), ExAC rs749663550, gnomAD rs749663550, MetaLR 0.08, MetaSVM -1.03
- F40S (p.Phe40Ser), cosmic curated COSV10586, MetaLR 0.03, MetaSVM -1.07
- F40F (p.Phe40Phe), rs1257454023, gnomAD 6-137871347-T-C, CADD 13.30
- K41E (p.Lys41Glu), TOPMed rs1776053092, MetaLR 0.02, MetaSVM -1.07
- T42I (p.Thr42Ile), NCI-TCGA TCGA novel, MetaLR 0.04, MetaSVM -1.12, Variant assessed as somatic; moderate impact.
- T42S (p.Thr42Ser), rs370854824, ClinGen CA4019350, ClinVar RCV002953425, ClinVar RCV005281268, MetaLR 0.03, MetaSVM -1.05, Benign/Likely benign, Inborn genetic diseases; not provided
- T42T (p.Thr42Thr), gnomAD 6-137871353-C-T, CADD 13.00
- M43I (p.Met43Ile), Ensembl rs2114459068, MetaLR 0.11, MetaSVM -1.05, Uncertain significance, not provided
- M43T (p.Met43Thr), gnomAD 6-137871355-T-C, CADD 26.30, PolyPhen-2 1.00
- H44Y (p.His44Tyr), gnomAD rs1478172750, MetaLR 0.11, MetaSVM -1.06
- R45* (p.Arg45Ter), rs1173941971, ClinGen CA365780410, cosmic curated COSV52801, ClinVar RCV001946977, CADD 36.00, Pathogenic
- R45Q (p.Arg45Gln), rs1422470027, ClinGen CA365780422, ClinVar RCV002771142, TOPMed rs1422470027, MetaLR 0.11, MetaSVM -1.08, Likely benign, not provided
- R45R (p.Arg45Arg), rs1173941971, gnomAD 6-137871360-C-A, CADD 13.40
- Y46* (p.Tyr46Ter), cosmic curated COSV10605, cosmic curated COSV10458, cosmic curated COSV10510
- Y46C (p.Tyr46Cys), Ensembl rs866569497
- Y46F (p.Tyr46Phe), cosmic curated COSV10586
- Y46H (p.Tyr46His), TOPMed rs1776054357, MetaLR 0.07, MetaSVM -1.04
- Y46Y (p.Tyr46Tyr), rs1011017009, gnomAD 6-137871365-C-T, CADD 9.29
- T47I (p.Thr47Ile), Ensembl rs2114459214
- T47R (p.Thr47Arg), cosmic curated COSV10437, MetaLR 0.08, MetaSVM -1.03
- T47T (p.Thr47Thr), rs774689592, gnomAD 6-137871368-A-C, CADD 2.28
- L48M (p.Leu48Met), gnomAD rs1171070280, MetaLR 0.03, MetaSVM -1.08, Uncertain significance, not provided
- L48L (p.Leu48Leu), gnomAD 6-137871369-C-T, CADD 11.90
- E49E (p.Glu49Glu), rs1776055466, gnomAD 6-137871374-A-G, CADD 11.80
- M50V (p.Met50Val), gnomAD 6-137871375-A-G, CADD 22.60, PolyPhen-2 0.39
- F51L (p.Phe51Leu), TOPMed rs1776055571, MetaLR 0.02, MetaSVM -1.07
- R52S (p.Arg52Ser), gnomAD rs1372271681, MetaLR 0.02, MetaSVM -1.06
- R52T (p.Arg52Thr), rs2482708655, ClinGen CA365780511, ClinVar RCV002935974, Uncertain significance
- T53I (p.Thr53Ile), cosmic curated COSV10804, Ensembl rs2114459340
- T53S (p.Thr53Ser), rs2114459340, ClinGen CA365780519, ClinVar RCV002846628, AlphaMissense 0.25, MetaLR 0.01, Uncertain significance, not provided
- C54* (p.Cys54Ter), cosmic curated COSV52800
- C54F (p.Cys54Phe), gnomAD rs1407911658, MetaLR 0.08, MetaSVM -1.11
- C54W (p.Cys54Trp), Ensembl rs2114459373
- C54Y (p.Cys54Tyr), cosmic curated COSV52798, gnomAD rs1407911658, MetaLR 0.08, MetaSVM -1.12
- Q55* (p.Gln55Ter), rs1776055887, ClinGen CA365780529, cosmic curated COSV10510, ClinVar RCV001310938, Likely pathogenic
- Q55P (p.Gln55Pro), TOPMed rs1776055989, MetaLR 0.06, MetaSVM -1.10
- Q55H (p.Gln55His), gnomAD 6-137871392-G-T, CADD 21.20, PolyPhen-2 0.01
- F56Y (p.Phe56Tyr), Ensembl rs1776056086, MetaLR 0.10, MetaSVM -1.00
- C57G (p.Cys57Gly), TOPMed rs1776056180
- C57S (p.Cys57Ser), TOPMed rs1776056180, MetaLR 0.02, MetaSVM -1.03
- C57F (p.Cys57Phe), gnomAD 6-137871397-G-T, CADD 24.40, PolyPhen-2 0.66
- C57C (p.Cys57Cys), gnomAD 6-137871398-T-C, CADD 8.28
- P58A (p.Pro58Ala), cosmic curated COSV52798
- P58L (p.Pro58Leu), cosmic curated COSV10586, MetaLR 0.02, MetaSVM -1.04
- P58T (p.Pro58Thr), rs529257107, ClinGen CA4019352, ClinVar RCV002015431, ClinVar RCV003269064, MetaLR 0.03, MetaSVM -1.10, Uncertain significance, Inborn genetic diseases; not provided
- P58P (p.Pro58Pro), rs772369780, gnomAD 6-137871401-T-G, CADD 3.05
- Q59* (p.Gln59Ter), Ensembl rs2114459550, CADD 36.00
- Q59H (p.Gln59His), TOPMed rs1776057105, MetaLR 0.02, MetaSVM -1.07
- Q59R (p.Gln59Arg), gnomAD 6-137871403-A-G, CADD 17.80, PolyPhen-2 0.24
- F60Y (p.Phe60Tyr), gnomAD 6-137871406-T-A, CADD 24.90, PolyPhen-2 0.99
Public TNFAIP3 analysis runs
- TNFAIP3 analysis run — TNFAIP3 (1,799 variants) — completed 2026-08-18