UBQLN2 (Ubiquilin-2) variants and mutations
UBQLN2 (also known as Ubiquilin-2) is a human protein-coding gene encoding an ubiquilin-2 protein. It shuttles ubiquitinated proteins toward proteasomal or autophagic degradation and helps maintain protein quality in neurons. Dominant X-linked variants can cause amyotrophic lateral sclerosis with or without frontotemporal dementia through impaired proteostasis. This analysis covers 1,019 UBQLN2 variants and mutations. Of these, 94% have computational variant effect predictions. Disease context includes amyotrophic lateral sclerosis type 15, amyotrophic lateral sclerosis, and familial amyotrophic lateral sclerosis. Example UBQLN2 variants include A2S, A2T, and A2D.
Variant analysis overview
- Gene: UBQLN2
- Protein: Ubiquilin-2
- UniProt accession: Q9UHD9
- Organism: Homo sapiens
- Variants analyzed: 1019
- Variant scope: all variants
- Completed: 2026-08-21
Variant and mutation evidence
- Variant composition: 497 unspecified-consequence records; 266 missense variants; 219 synonymous variants; 6 stop-gained variants; 12 in-frame deletions; 15 frameshift variants; 1 in-frame insertions; 3 substitution
- Prediction scores: 955 variants have prediction scores (94% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: amyotrophic lateral sclerosis type 15, amyotrophic lateral sclerosis, familial amyotrophic lateral sclerosis, amyotrophic lateral sclerosis, dominant, hypertensive disorder, vascular dementia, frontotemporal dementia, Alzheimer disease, lung adenocarcinoma, neoplasm, hepatocellular carcinoma, esophageal squamous cell carcinoma.
Protein structure and variant hotspots
- Protein features: 6 domains; 1 post-translational modification sites.
- Structural context: 335 variants have structural context.
- PTM context: 5 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 UBQLN2 variants
Examples include A2S, A2T, A2D, A2V, A2A, E3D, E3K, E3G. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- A2S (p.Ala2Ser), rs779715794, ClinGen CA10430029, ClinVar RCV003118500, ExAC rs779715794, REVEL 0.13, CADD 23.60, Uncertain significance, Amyotrophic lateral sclerosis type 15
- A2T (p.Ala2Thr), gnomAD X-56563877-G-A, REVEL 0.15, MetaLR 0.14
- A2D (p.Ala2Asp), gnomAD X-56563878-C-A, REVEL 0.17, MetaLR 0.20
- A2V (p.Ala2Val), gnomAD X-56563878-C-T, REVEL 0.16, MetaLR 0.12
- A2A (p.Ala2Ala), gnomAD X-56563879-T-A, CADD 16.00
- E3D (p.Glu3Asp), TOPMed rs1020896571, REVEL 0.05, CADD 22.80
- E3K (p.Glu3Lys), gnomAD X-56563880-G-A, REVEL 0.19, MetaLR 0.15
- E3G (p.Glu3Gly), gnomAD X-56563881-A-G, REVEL 0.23, MetaLR 0.15
- E3E (p.Glu3Glu), gnomAD X-56563882-G-A, CADD 13.50
- N4D (p.Asn4Asp), gnomAD X-56563883-A-G, REVEL 0.12, MetaLR 0.09
- N4S (p.Asn4Ser), gnomAD X-56563884-A-G, REVEL 0.12, MetaLR 0.06
- N4K (p.Asn4Lys), gnomAD X-56563885-T-G, REVEL 0.07, MetaLR 0.06
- G5R (p.Gly5Arg), gnomAD X-56563886-G-C, REVEL 0.18, MetaLR 0.22
- G5D (p.Gly5Asp), gnomAD X-56563887-G-A, REVEL 0.17, MetaLR 0.22
- G5G (p.Gly5Gly), gnomAD X-56563888-C-T, CADD 14.10
- E6K (p.Glu6Lys), gnomAD rs1186772253, MetaLR 0.08, MetaSVM -0.95
- E6* (p.Glu6Ter), gnomAD X-56563889-G-T, CADD 35.00
- E6D (p.Glu6Asp), gnomAD X-56563891-G-T, REVEL 0.07, MetaLR 0.07
- S7N (p.Ser7Asn), gnomAD rs1412665727, REVEL 0.08, CADD 19.40
- S7R (p.Ser7Arg), rs202132872, ClinGen CA10430030, ClinVar RCV002020808, 1000Genomes rs202132872, REVEL 0.13, CADD 22.90, Uncertain significance, Amyotrophic lateral sclerosis type 15
- S7G (p.Ser7Gly), gnomAD X-56563892-A-G, REVEL 0.10, MetaLR 0.06
- S7I (p.Ser7Ile), gnomAD X-56563893-G-T, REVEL 0.08, MetaLR 0.05
- S8G (p.Ser8Gly), gnomAD X-56563895-A-G, REVEL 0.04, MetaLR 0.04
- S8S (p.Ser8Ser), rs2068628293, gnomAD X-56563897-C-T, CADD 14.60
- G9S (p.Gly9Ser), TOPMed rs2068628316, REVEL 0.12, CADD 22.70
- G9V (p.Gly9Val), gnomAD rs2068628337, REVEL 0.07, CADD 23.40
- G9R (p.Gly9Arg), gnomAD X-56563898-G-C, REVEL 0.09, MetaLR 0.07
- G9D (p.Gly9Asp), gnomAD X-56563899-G-A, REVEL 0.12, MetaLR 0.04
- G9G (p.Gly9Gly), rs754777429, gnomAD X-56563900-C-G, CADD 13.80
- P10T (p.Pro10Thr), gnomAD X-56563901-C-A, REVEL 0.15, MetaLR 0.12
- P10S (p.Pro10Ser), gnomAD X-56563901-C-T, REVEL 0.15, MetaLR 0.12
- P10L (p.Pro10Leu), gnomAD X-56563902-C-T, REVEL 0.10, MetaLR 0.12
- P10P (p.Pro10Pro), rs2068628385, gnomAD X-56563903-C-T, CADD 15.00
- P11L (p.Pro11Leu), ExAC rs778646844, TOPMed rs778646844, REVEL 0.07, CADD 23.50
- P11Q (p.Pro11Gln), ExAC rs778646844, TOPMed rs778646844, REVEL 0.07, CADD 24.70
- p.Pro11 Pro17del, rs766137036, gnomAD X-56563895-AGCGGC, CADD 19.90
- P11R (p.Pro11Arg), gnomAD X-56563899-GC-G, CADD 23.90
- P11T (p.Pro11Thr), gnomAD X-56563904-C-A, REVEL 0.05, MetaLR 0.06
- P11P (p.Pro11Pro), rs748108475, gnomAD X-56563906-G-T, CADD 13.90
- R12H (p.Arg12His), NCI-TCGA Cosmic COSV5773, Variant assessed as somatic; moderate impact.
- R12L (p.Arg12Leu), TOPMed rs1301101998, gnomAD rs1301101998, REVEL 0.03, CADD 18.60
- R12A (p.Arg12Ala), rs1385308098, gnomAD X-56563899-G-GC, CADD 26.70
- R12C (p.Arg12Cys), gnomAD X-56563907-C-T, REVEL 0.06, MetaLR 0.05
- R12P (p.Arg12Pro), gnomAD X-56563908-G-C, REVEL 0.16, MetaLR 0.06
- P13S (p.Pro13Ser), gnomAD X-56563910-C-T, REVEL 0.09, MetaLR 0.05
- P13T (p.Pro13Thr), gnomAD X-56563910-C-A, REVEL 0.10, MetaLR 0.05
- P13P (p.Pro13Pro), rs771958308, gnomAD X-56563912-C-A, CADD 13.90
- S14P (p.Ser14Pro), gnomAD X-56563913-T-C, REVEL 0.20, MetaLR 0.07
- S14Y (p.Ser14Tyr), gnomAD X-56563914-C-A, REVEL 0.15, MetaLR 0.11
- S14S (p.Ser14Ser), rs999138602, gnomAD X-56563915-C-T, CADD 14.10
- R15C (p.Arg15Cys), gnomAD rs1289794590, REVEL 0.12, CADD 25.80
- R15H (p.Arg15His), NCI-TCGA Cosmic COSV1005, REVEL 0.12, CADD 22.90, Variant assessed as somatic; moderate impact.
- R15L (p.Arg15Leu), gnomAD X-56563917-G-T, REVEL 0.17, MetaLR 0.07
- R15R (p.Arg15Arg), gnomAD X-56563918-C-A, CADD 13.00
- G16S (p.Gly16Ser), TOPMed rs1370164891, gnomAD rs1370164891, REVEL 0.11, CADD 23.30
- G16C (p.Gly16Cys), gnomAD X-56563919-G-T, REVEL 0.17, MetaLR 0.14
- G16D (p.Gly16Asp), gnomAD X-56563920-G-A, REVEL 0.14, MetaLR 0.11
- G16G (p.Gly16Gly), rs2068628505, gnomAD X-56563921-C-T, CADD 13.80
- P17A (p.Pro17Ala), gnomAD rs1378794338, REVEL 0.01, AlphaMissense 0.05
- P17S (p.Pro17Ser), rs1378794338, ClinGen CA413377458, ClinVar RCV003088473, AlphaMissense 0.05, MetaLR 0.05, Uncertain significance, Amyotrophic lateral sclerosis type 15
- P17H (p.Pro17His), gnomAD X-56563923-C-A, REVEL 0.05, MetaLR 0.05
- P17R (p.Pro17Arg), gnomAD X-56563923-C-G, REVEL 0.03, MetaLR 0.05
- P17P (p.Pro17Pro), rs371163085, gnomAD X-56563924-T-A, CADD 14.30
- A18D (p.Ala18Asp), NCI-TCGA TCGA novel, REVEL 0.07, CADD 22.40, Variant assessed as somatic; moderate impact.
- A18V (p.Ala18Val), gnomAD rs1317265713, REVEL 0.06, CADD 22.40
- A18T (p.Ala18Thr), gnomAD X-56563925-G-A, REVEL 0.07, MetaLR 0.05
- A18S (p.Ala18Ser), gnomAD X-56563925-G-T, REVEL 0.06, MetaLR 0.05
- A18A (p.Ala18Ala), gnomAD X-56563927-T-C, CADD 11.80
- A19V (p.Ala19Val), rs2146635566, ClinGen CA413377473, ClinVar RCV001944256, Ensembl rs2146635566, REVEL 0.07, CADD 20.90, Uncertain significance, Amyotrophic lateral sclerosis type 15
- A19E (p.Ala19Glu), gnomAD X-56563929-C-A, REVEL 0.15, MetaLR 0.09
- A19A (p.Ala19Ala), rs771236062, gnomAD X-56563930-G-A, CADD 13.70
- A20S (p.Ala20Ser), ExAC rs777013943, TOPMed rs777013943, gnomAD rs777013943, REVEL 0.06, CADD 19.40
- A20T (p.Ala20Thr), gnomAD X-56563931-G-A, REVEL 0.07, MetaLR 0.05
- A20D (p.Ala20Asp), gnomAD X-56563932-C-A, REVEL 0.10, MetaLR 0.05
- A20V (p.Ala20Val), gnomAD X-56563932-C-T, REVEL 0.10, MetaLR 0.05
- A20A (p.Ala20Ala), gnomAD X-56563933-C-A, CADD 13.00
- Q21R (p.Gln21Arg), TOPMed rs921325444, REVEL 0.04, CADD 7.88
- p.Gln21 Ala26del, gnomAD X-56563924-TGCTGC, CADD 19.30
- Q21K (p.Gln21Lys), gnomAD X-56563934-C-A, REVEL 0.06, MetaLR 0.05
- Q21P (p.Gln21Pro), gnomAD X-56563935-A-C, REVEL 0.05, MetaLR 0.05
- Q21Q (p.Gln21Gln), gnomAD X-56563936-A-G, CADD 9.13
- G22G (p.Gly22Gly), gnomAD X-56563939-C-A, CADD 8.92
- S23P (p.Ser23Pro), gnomAD X-56563940-T-C, REVEL 0.04, MetaLR 0.04
- S23* (p.Ser23Ter), gnomAD X-56563941-C-A, CADD 32.00
- S23S (p.Ser23Ser), gnomAD X-56563942-G-T, CADD 2.37
- A24L (p.Ala24Leu), NCI-TCGA TCGA novel, MetaLR 0.04, MetaSVM -1.02, Variant assessed as somatic; high impact.
- A24P (p.Ala24Pro), gnomAD X-56563943-G-C, REVEL 0.05, MetaLR 0.04
- A24D (p.Ala24Asp), gnomAD X-56563944-C-A, REVEL 0.08, MetaLR 0.05
- A24G (p.Ala24Gly), gnomAD X-56563944-C-G, REVEL 0.10, MetaLR 0.05
- A25A (p.Ala25Ala), rs892166449, gnomAD X-56563948-T-C, CADD 5.76
- A26S (p.Ala26Ser), rs2519961524, ClinGen CA413377512, ClinVar RCV003525603, ClinVar RCV005220743, REVEL 0.02, CADD 1.13, Uncertain significance, not provided; Amyotrophic lateral sclerosis type 15
- A26V (p.Ala26Val), gnomAD rs954030275, REVEL 0.03, CADD 15.50
- A26T (p.Ala26Thr), gnomAD X-56563949-G-A, REVEL 0.03, MetaLR 0.04
- A26D (p.Ala26Asp), gnomAD X-56563950-C-A, REVEL 0.05, MetaLR 0.06
- P27L (p.Pro27Leu), TOPMed rs1442285695, gnomAD rs1442285695, REVEL 0.01, CADD 2.38, Uncertain significance, not specified
- P27T (p.Pro27Thr), gnomAD rs1236664140, REVEL 0.02, CADD 1.03
- P27P (p.Pro27Pro), gnomAD X-56563954-G-T, CADD 2.03
- A28D (p.Ala28Asp), Ensembl rs2068628797, MetaLR 0.05, MetaSVM -1.04
- A28P (p.Ala28Pro), rs1459753673, ClinGen CA413377522, ClinVar RCV001919418, ClinVar RCV004753430, REVEL 0.03, CADD 10.30, Uncertain significance, Amyotrophic lateral sclerosis type 15
- A28T (p.Ala28Thr), gnomAD X-56563955-G-A, REVEL 0.05, MetaLR 0.04
- A28S (p.Ala28Ser), gnomAD X-56563955-G-T, REVEL 0.03, MetaLR 0.04
- A28V (p.Ala28Val), gnomAD X-56563956-C-T, REVEL 0.06, MetaLR 0.05
- A28A (p.Ala28Ala), gnomAD X-56563957-T-C, CADD 3.18
- E29K (p.Glu29Lys), TOPMed rs1184902272, gnomAD rs1184902272, REVEL 0.11, CADD 21.10
- E29V (p.Glu29Val), TOPMed rs1385545278, gnomAD rs1385545278, REVEL 0.16, CADD 23.00
- I32L (p.Ile32Leu), TOPMed rs1013330770, MetaLR 0.11, MetaSVM -0.94
- I32S (p.Ile32Ser), gnomAD X-56563963-TA-T, CADD 23.40
- I32V (p.Ile32Val), gnomAD X-56563967-A-G, REVEL 0.12, MetaLR 0.09
- I32I (p.Ile32Ile), gnomAD X-56563969-C-A, CADD 13.00
- K34K (p.Lys34Lys), gnomAD X-56563975-A-G, CADD 14.60
- T36M (p.Thr36Met), gnomAD X-56563980-C-T, REVEL 0.33, MetaLR 0.31
- K38N (p.Lys38Asn), NCI-TCGA Cosmic COSV5773, MetaLR 0.69, MetaSVM 0.37, Variant assessed as somatic; moderate impact.
- K38M (p.Lys38Met), gnomAD X-56563986-A-T, REVEL 0.83, MetaLR 0.72
- T39N (p.Thr39Asn), gnomAD X-56563989-C-A, REVEL 0.60, MetaLR 0.61
- T39T (p.Thr39Thr), gnomAD X-56563990-T-C, CADD 13.20
- P40H (p.Pro40His), gnomAD X-56563992-C-A, REVEL 0.62, MetaLR 0.67
- P40P (p.Pro40Pro), gnomAD X-56563993-C-A, CADD 12.30
- K41I (p.Lys41Ile), Ensembl rs2068628875, MetaLR 0.26, MetaSVM -0.58
- K41R (p.Lys41Arg), gnomAD X-56563995-A-G, REVEL 0.19, MetaLR 0.19
- E42D (p.Glu42Asp), gnomAD rs1184980400, REVEL 0.14, CADD 14.50
- E42Q (p.Glu42Gln), NCI-TCGA TCGA novel, MetaLR 0.26, MetaSVM -0.51, Variant assessed as somatic; moderate impact.
- E42* (p.Glu42Ter), gnomAD X-56563997-G-T, CADD 35.00
- E42G (p.Glu42Gly), gnomAD X-56563998-A-G, REVEL 0.27, MetaLR 0.25
- E42V (p.Glu42Val), gnomAD X-56563998-A-T, REVEL 0.44, MetaLR 0.42
- K43E (p.Lys43Glu), NCI-TCGA TCGA novel, MetaLR 0.51, MetaSVM 0.02, Variant assessed as somatic; moderate impact.
- K43R (p.Lys43Arg), gnomAD X-56564001-A-G, REVEL 0.48, MetaLR 0.56
- E44* (p.Glu44Ter), NCI-TCGA Cosmic COSV5773, Variant assessed as somatic; high impact.
- E44G (p.Glu44Gly), gnomAD X-56564004-A-G, REVEL 0.54, MetaLR 0.47
- E44E (p.Glu44Glu), gnomAD X-56564005-G-A, CADD 13.10
- E45D (p.Glu45Asp), gnomAD X-56564008-G-T, REVEL 0.12, MetaLR 0.16
- E45E (p.Glu45Glu), gnomAD X-56564008-G-A, CADD 11.70
- F46I (p.Phe46Ile), NCI-TCGA Cosmic COSV1005, NCI-TCGA Cosmic COSV5773, REVEL 0.39, CADD 22.10, Variant assessed as somatic; moderate impact.
- F46L (p.Phe46Leu), gnomAD X-56564011-C-A, REVEL 0.37, MetaLR 0.30
- A47S (p.Ala47Ser), gnomAD X-56564012-G-T, REVEL 0.20, MetaLR 0.18
- A47E (p.Ala47Glu), gnomAD X-56564013-C-A, REVEL 0.29, MetaLR 0.14
- A47V (p.Ala47Val), gnomAD X-56564013-C-T, REVEL 0.24, MetaLR 0.27
- A47A (p.Ala47Ala), rs143098023, gnomAD X-56564014-G-A, CADD 9.80
- V48M (p.Val48Met), gnomAD X-56564015-G-A, REVEL 0.72, MetaLR 0.68
- V48V (p.Val48Val), rs1438489280, gnomAD X-56564017-G-A, CADD 11.90
- P49S (p.Pro49Ser), TOPMed rs969212678, REVEL 0.14, CADD 17.00
- P49H (p.Pro49His), gnomAD X-56564019-C-A, REVEL 0.24, MetaLR 0.39
- P49L (p.Pro49Leu), gnomAD X-56564019-C-T, REVEL 0.25, MetaLR 0.38
- P49P (p.Pro49Pro), rs1254959794, gnomAD X-56564020-C-T, CADD 8.38
- E50D (p.Glu50Asp), TOPMed rs1156273861, gnomAD rs1156273861, REVEL 0.21, CADD 15.00, Likely benign
- E50* (p.Glu50Ter), gnomAD X-56564021-G-T, CADD 34.00
- E50E (p.Glu50Glu), rs1156273861, gnomAD X-56564023-G-A, CADD 11.00
- N51D (p.Asn51Asp), TOPMed rs2068629024, MetaLR 0.09, MetaSVM -0.92
- S52G (p.Ser52Gly), Ensembl rs2146635614, MetaLR 0.38, MetaSVM -0.34
- S52I (p.Ser52Ile), gnomAD rs2068629041, REVEL 0.39, CADD 22.80
- S53L (p.Ser53Leu), NCI-TCGA Cosmic COSV5773, REVEL 0.45, CADD 24.30, Variant assessed as somatic; moderate impact.
- S53* (p.Ser53Ter), gnomAD X-56564031-C-A, CADD 33.00
- S53S (p.Ser53Ser), rs772580178, gnomAD X-56564032-G-T, CADD 8.78
- V54I (p.Val54Ile), gnomAD X-56564033-G-A, REVEL 0.14, MetaLR 0.13
- Q55H (p.Gln55His), gnomAD X-56564038-G-T, REVEL 0.26, MetaLR 0.36
- Q55Q (p.Gln55Gln), rs763496311, gnomAD X-56564038-G-A, CADD 11.70
- Q56K (p.Gln56Lys), gnomAD X-56564039-C-A, REVEL 0.27, MetaLR 0.33
- Q56Q (p.Gln56Gln), rs764551691, gnomAD X-56564041-G-A, CADD 11.30
- F57L (p.Phe57Leu), Ensembl rs2068629124, NCI-TCGA TCGA novel, REVEL 0.28, CADD 23.80, Uncertain significance, Amyotrophic lateral sclerosis type 15
- K58Q (p.Lys58Gln), NCI-TCGA TCGA novel, MetaLR 0.90, MetaSVM 1.00, Variant assessed as somatic; moderate impact.
- K58K (p.Lys58Lys), rs760204159, gnomAD X-56564047-G-A, CADD 12.40
- E59K (p.Glu59Lys), gnomAD rs1338894348, MetaLR 0.52, MetaSVM -0.02
- E59E (p.Glu59Glu), gnomAD X-56564050-A-G, CADD 14.10
- A60E (p.Ala60Glu), 1000Genomes rs368346745, ESP rs368346745, ExAC rs368346745, TOPMed rs368346745, REVEL 0.20, CADD 18.80
- A60T (p.Ala60Thr), NCI-TCGA TCGA novel, MetaLR 0.23, MetaSVM -0.79, Variant assessed as somatic; moderate impact.
- A60V (p.Ala60Val), 1000Genomes rs368346745, ESP rs368346745, ExAC rs368346745, TOPMed rs368346745, REVEL 0.18, CADD 22.80, Uncertain significance, Amyotrophic lateral sclerosis type 15
- A60G (p.Ala60Gly), gnomAD X-56564052-C-G, REVEL 0.27, MetaLR 0.31
- S62L (p.Ser62Leu), NCI-TCGA Cosmic COSV5774, REVEL 0.62, CADD 27.00, Variant assessed as somatic; moderate impact.
- S62S (p.Ser62Ser), rs753490349, gnomAD X-56564059-G-A, CADD 6.53
- K63N (p.Lys63Asn), gnomAD rs939897674, REVEL 0.32, CADD 25.60
- K63R (p.Lys63Arg), TOPMed rs1341538948, gnomAD rs1341538948, REVEL 0.15, CADD 22.00
- R64S (p.Arg64Ser), Ensembl rs2146635652, MetaLR 0.42, MetaSVM -0.40
- R64L (p.Arg64Leu), gnomAD X-56564064-G-T, REVEL 0.67, MetaLR 0.47
- R64H (p.Arg64His), gnomAD X-56564064-G-A, REVEL 0.51, MetaLR 0.36
- F65F (p.Phe65Phe), rs754649110, gnomAD X-56564068-C-T, CADD 14.40
- S67S (p.Ser67Ser), gnomAD X-56564074-C-T, CADD 13.00
- Q68E (p.Gln68Glu), TOPMed rs1394576923, gnomAD rs1394576923, REVEL 0.05, CADD 18.40, Uncertain significance, UBQLN2-related disorder
- T69T (p.Thr69Thr), gnomAD X-56564080-C-G, CADD 10.70
- D70N (p.Asp70Asn), TOPMed rs200184714, gnomAD rs200184714, REVEL 0.27, CADD 29.10
- Q71L (p.Gln71Leu), NCI-TCGA TCGA novel, MetaLR 0.56, MetaSVM 0.14, Variant assessed as somatic; high impact.
- Q71K (p.Gln71Lys), gnomAD X-56564084-C-A, REVEL 0.62, MetaLR 0.59
Public UBQLN2 analysis runs
- UBQLN2 analysis run — UBQLN2 (1,019 variants) — completed 2026-08-21