CLCN5 (P51795) variants and mutations
CLCN5 (also known as P51795) is a human protein-coding gene encoding a h(+)/Cl(-) exchange transporter 5 protein. It supports endosomal acidification and receptor recycling in renal proximal-tubule cells, enabling efficient reabsorption of filtered proteins and solutes. Loss-of-function variants cause Dent disease type 1, with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, and kidney-stone risk. This analysis covers 976 CLCN5 variants and mutations. Of these, 68% have computational variant effect predictions. Disease context includes Dent disease type 1, Dent disease, and hypophosphatemic rickets, X-linked recessive. Example CLCN5 variants include M1V, A2T, and A2V.
Variant analysis overview
- Gene: CLCN5
- Protein: P51795
- UniProt accession: P51795
- Organism: Homo sapiens
- Variants analyzed: 976
- Variant scope: all variants
- Completed: 2026-08-20
Variant and mutation evidence
- Variant composition: 706 unspecified-consequence records; 150 missense variants; 5 splice-region variants; 18 frameshift variants; 76 synonymous variants; 7 stop-gained variants; 3 in-frame deletions; 2 stop lost; 1 stop retained variant; 1 in-frame insertions; 7 substitution
- Prediction scores: 664 variants have prediction scores (68% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: Dent disease type 1, Dent disease, hypophosphatemic rickets, X-linked recessive, proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis, hypophosphatemic rickets, hereditary disease, nephrotic syndrome, X-linked hypophosphatemia, X-linked dominant hypophosphatemic rickets, Low-molecular-weight proteinuria, Multiple small medullary renal cysts, Hyperkalemia.
Protein structure and variant hotspots
- Protein features: 10 transmembrane segments; 2 domains; 6 binding sites.
- Structural context: 302 variants have structural context.
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 CLCN5 variants
Examples include M1V, A2T, A2V, M3T, M3V, W4*, W4R, W4S. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- M1V (p.Met1Val), rs2519188777, ClinGen CA413175949, ClinVar RCV002472296, Uncertain significance, Dent disease type 1
- A2T (p.Ala2Thr), rs868953478, Ensembl rs868953478, REVEL 0.41, MetaLR 0.70, Variant assessed as somatic; moderate impact.
- A2V (p.Ala2Val), gnomAD X-49925303-C-T, REVEL 0.41, MetaLR 0.70
- M3T (p.Met3Thr), TOPMed rs1310442729, gnomAD rs1310442729, REVEL 0.19, MetaLR 0.49
- M3V (p.Met3Val), ExAC rs782073023, gnomAD rs782073023, REVEL 0.29, MetaLR 0.50
- W4* (p.Trp4Ter), NCI-TCGA Cosmic COSV6580, cosmic curated COSV65800, CADD 35.00, Variant assessed as somatic; high impact.
- W4R (p.Trp4Arg), cosmic curated COSV10106
- W4S (p.Trp4Ser), ExAC rs782798617, TOPMed rs782798617, gnomAD rs782798617, REVEL 0.44, MetaLR 0.67
- Q5Q (p.Gln5Gln), gnomAD X-49925313-G-A, CADD 12.00
- G6D (p.Gly6Asp), TOPMed rs1932249929, REVEL 0.46, MetaLR 0.75
- G6C (p.Gly6Cys), gnomAD X-49925314-G-T, REVEL 0.57, MetaLR 0.78
- G6G (p.Gly6Gly), gnomAD X-50042317-T-A, CADD 7.71
- A7T (p.Ala7Thr), gnomAD X-50042318-G-A, REVEL 0.21, MetaLR 0.52
- A7S (p.Ala7Ser), gnomAD X-50042318-G-T, REVEL 0.20, MetaLR 0.51
- A7P (p.Ala7Pro), gnomAD X-50042318-G-C, REVEL 0.20, MetaLR 0.58
- A7V (p.Ala7Val), gnomAD X-50042319-C-T, REVEL 0.30, MetaLR 0.57
- A7G (p.Ala7Gly), gnomAD X-50042319-C-G, REVEL 0.26, MetaLR 0.49
- A7D (p.Ala7Asp), gnomAD X-50042319-C-A, REVEL 0.33, MetaLR 0.57
- A7A (p.Ala7Ala), gnomAD X-50042320-C-T, CADD 11.40
- M8I (p.Met8Ile), cosmic curated COSV65803, cosmic curated COSV10592, REVEL 0.50, MetaLR 0.73
- M8V (p.Met8Val), ExAC rs781863873, gnomAD rs781863873, REVEL 0.41, MetaLR 0.67
- M8W (p.Met8Trp), gnomAD X-50042318-GC-G, CADD 24.10
- M8T (p.Met8Thr), gnomAD X-50042322-T-C, REVEL 0.52, MetaLR 0.77
- M8K (p.Met8Lys), gnomAD X-50042322-T-A, REVEL 0.60, MetaLR 0.78
- D9Y (p.Asp9Tyr), cosmic curated COSV10749, Ensembl rs1557187248, REVEL 0.59, MetaLR 0.70
- D9N (p.Asp9Asn), gnomAD X-50042324-G-A, REVEL 0.30, MetaLR 0.54
- D9G (p.Asp9Gly), gnomAD X-50042325-A-G, REVEL 0.43, MetaLR 0.58
- D9V (p.Asp9Val), gnomAD X-50042325-A-T, REVEL 0.52, MetaLR 0.60
- D9E (p.Asp9Glu), gnomAD X-50042326-T-A, REVEL 0.15, MetaLR 0.49
- N10D (p.Asn10Asp), gnomAD X-50042327-A-G, REVEL 0.19, MetaLR 0.43
- N10N (p.Asn10Asn), gnomAD X-50042329-C-T, CADD 7.85
- N10K (p.Asn10Lys), gnomAD X-50042329-C-A, REVEL 0.23, MetaLR 0.45
- R11T (p.Arg11Thr), Ensembl rs1932250495
- R11E (p.Arg11Glu), gnomAD X-50042329-CA-C, CADD 24.70
- R11I (p.Arg11Ile), gnomAD X-50042331-G-T, REVEL 0.17, MetaLR 0.46
- R11R (p.Arg11Arg), gnomAD X-50042332-A-G, CADD 13.60
- G12C (p.Gly12Cys), gnomAD X-50042333-G-T, REVEL 0.62, MetaLR 0.84
- G12S (p.Gly12Ser), gnomAD X-50042333-G-A, REVEL 0.56, MetaLR 0.80
- G12V (p.Gly12Val), gnomAD X-50042334-G-T, REVEL 0.56, MetaLR 0.84
- G12G (p.Gly12Gly), gnomAD X-50042335-C-T, CADD 10.70
- F13L (p.Phe13Leu), gnomAD X-50042336-T-C, REVEL 0.33, MetaLR 0.51
- F13S (p.Phe13Ser), gnomAD X-50042337-T-C, REVEL 0.27, MetaLR 0.57
- F13F (p.Phe13Phe), gnomAD X-50042338-T-C, CADD 12.80
- Q14R (p.Gln14Arg), TOPMed rs1557187251, gnomAD rs1557187251, REVEL 0.20, MetaLR 0.43
- Q14S (p.Gln14Ser), NCI-TCGA TCGA novel, Variant assessed as somatic; high impact.
- Q14K (p.Gln14Lys), gnomAD X-50042339-C-A, REVEL 0.21, MetaLR 0.49
- Q14* (p.Gln14Ter), gnomAD X-50042339-C-T, CADD 34.00
- Q14Q (p.Gln14Gln), gnomAD X-50042341-G-A, CADD 8.25
- Q15E (p.Gln15Glu), gnomAD rs1557187252
- Q15R (p.Gln15Arg), ExAC rs782084525, TOPMed rs782084525, gnomAD rs782084525, REVEL 0.24, MetaLR 0.34
- Q15* (p.Gln15Ter), gnomAD X-50042342-C-T, CADD 35.00
- Q15H (p.Gln15His), gnomAD X-50042344-G-T, REVEL 0.18, MetaLR 0.41
- Q15Q (p.Gln15Gln), gnomAD X-50042344-G-A, CADD 6.83
- G16E (p.Gly16Glu), gnomAD rs1557187256, REVEL 0.29, MetaLR 0.38
- G16R (p.Gly16Arg), gnomAD X-50042345-G-A, REVEL 0.40, MetaLR 0.46
- G16W (p.Gly16Trp), gnomAD X-50042345-G-T, REVEL 0.60, MetaLR 0.76
- G16V (p.Gly16Val), gnomAD X-50042346-G-T, REVEL 0.33, MetaLR 0.58
- G16A (p.Gly16Ala), gnomAD X-50042346-G-C, REVEL 0.29, MetaLR 0.44
- G16G (p.Gly16Gly), rs1932251426, gnomAD X-50042347-G-T, CADD 10.10
- S17N (p.Ser17Asn), NCI-TCGA TCGA novel, REVEL 0.51, MetaLR 0.82, Variant assessed as somatic; moderate impact.
- S17V (p.Ser17Val), gnomAD X-50042343-AG-A, CADD 22.00
- S17G (p.Ser17Gly), gnomAD X-50042348-A-G, REVEL 0.47, MetaLR 0.82
- F18I (p.Phe18Ile), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- F18V (p.Phe18Val), ExAC rs782744227, TOPMed rs782744227, gnomAD rs782744227, REVEL 0.22, MetaLR 0.51
- F18L (p.Phe18Leu), gnomAD X-50042349-GT-G, CADD 24.20
- F18S (p.Phe18Ser), gnomAD X-50042352-T-C, REVEL 0.29, MetaLR 0.60
- S19I (p.Ser19Ile), ExAC rs781788759, gnomAD rs781788759, REVEL 0.13, MetaLR 0.46
- S19N (p.Ser19Asn), ExAC rs781788759, gnomAD rs781788759, REVEL 0.19, MetaLR 0.38
- S19G (p.Ser19Gly), gnomAD X-50042354-A-G, REVEL 0.27, MetaLR 0.49
- S19R (p.Ser19Arg), gnomAD X-50042356-T-A, REVEL 0.14, MetaLR 0.42
- S19S (p.Ser19Ser), gnomAD X-50042356-T-C, CADD 12.80
- S20I (p.Ser20Ile), gnomAD rs960373474, REVEL 0.43, MetaLR 0.83
- S20T (p.Ser20Thr), gnomAD rs960373474
- S20C (p.Ser20Cys), gnomAD X-50042357-A-T, REVEL 0.54, MetaLR 0.83
- S20G (p.Ser20Gly), gnomAD X-50042357-A-G, REVEL 0.42, MetaLR 0.78
- S20N (p.Ser20Asn), gnomAD X-50042358-G-A, REVEL 0.39, MetaLR 0.81
- S20S (p.Ser20Ser), gnomAD X-50042359-C-T, CADD 12.10
- S20R (p.Ser20Arg), gnomAD X-50042359-C-A, REVEL 0.47, MetaLR 0.76
- F21L (p.Phe21Leu), cosmic curated COSV65799, REVEL 0.19, MetaLR 0.40
- F21* (p.Phe21Ter), rs1557187265, gnomAD X-50042360-TTCCA-, CADD 24.60
- F21F (p.Phe21Phe), gnomAD X-50042362-C-T, CADD 10.60
- Q22R (p.Gln22Arg), gnomAD rs991814636, REVEL 0.21, MetaLR 0.42
- Q22* (p.Gln22Ter), gnomAD X-50042363-C-T, CADD 35.00
- Q22K (p.Gln22Lys), gnomAD X-50042363-C-A, REVEL 0.23, MetaLR 0.42
- Q22Q (p.Gln22Gln), gnomAD X-50042365-G-A, CADD 8.99
- Q22H (p.Gln22His), gnomAD X-50042365-G-T, REVEL 0.13, MetaLR 0.43
- N23S (p.Asn23Ser), TOPMed rs1258552575
- N23D (p.Asn23Asp), gnomAD X-50042366-A-G, REVEL 0.33, MetaLR 0.54
- N23N (p.Asn23Asn), gnomAD X-50042368-C-T, CADD 8.21
- N23K (p.Asn23Lys), gnomAD X-50042368-C-A, REVEL 0.21, MetaLR 0.51
- S24G (p.Ser24Gly), gnomAD rs1557187279, REVEL 0.20, MetaLR 0.48
- S24I (p.Ser24Ile), gnomAD X-50042370-G-T, REVEL 0.32, MetaLR 0.63
- S24N (p.Ser24Asn), gnomAD X-50042370-G-A, REVEL 0.24, MetaLR 0.50
- S24R (p.Ser24Arg), gnomAD X-50042371-C-A, REVEL 0.33, MetaLR 0.51
- S25F (p.Ser25Phe), gnomAD rs1557187281, REVEL 0.33, MetaLR 0.64
- S25P (p.Ser25Pro), TOPMed rs1193230721, REVEL 0.24, MetaLR 0.55
- p.Ser25 Ser26del, gnomAD X-50042367-ACAGCT, CADD 17.10
- S25Y (p.Ser25Tyr), gnomAD X-50042373-C-A, REVEL 0.41, MetaLR 0.67
- S25S (p.Ser25Ser), gnomAD X-50042374-C-A, CADD 9.30
- S26I (p.Ser26Ile), gnomAD X-50042376-G-T, REVEL 0.52, MetaLR 0.84
- S26T (p.Ser26Thr), gnomAD X-50042376-G-C, REVEL 0.47, MetaLR 0.78
- D27G (p.Asp27Gly), TOPMed rs1487310174, gnomAD rs1487310174, REVEL 0.59, MetaLR 0.81
- D27N (p.Asp27Asn), gnomAD X-50042378-G-A, REVEL 0.52, MetaLR 0.81
- D27Y (p.Asp27Tyr), gnomAD X-50042378-G-T, REVEL 0.68, MetaLR 0.85
- E28K (p.Glu28Lys), NCI-TCGA Cosmic COSV1010, cosmic curated COSV10106, REVEL 0.48, MetaLR 0.49, Variant assessed as somatic; moderate impact.
- E28E (p.Glu28Glu), gnomAD X-50042383-A-G, CADD 9.03
- D29N (p.Asp29Asn), gnomAD X-50042384-G-A, REVEL 0.41, MetaLR 0.59
- D29G (p.Asp29Gly), gnomAD X-50042385-A-G, REVEL 0.37, MetaLR 0.56
- D29D (p.Asp29Asp), gnomAD X-50042386-C-T, CADD 9.50
- D29E (p.Asp29Glu), gnomAD X-50042386-C-A, REVEL 0.31, MetaLR 0.37
- L30M (p.Leu30Met), cosmic curated COSV10106, REVEL 0.27, MetaLR 0.46
- L30P (p.Leu30Pro), gnomAD X-50042388-T-C, REVEL 0.55, MetaLR 0.66
- L30L (p.Leu30Leu), gnomAD X-50042389-G-T, CADD 8.47
- M31V (p.Met31Val), Ensembl rs916340219, REVEL 0.20, MetaLR 0.37
- M31L (p.Met31Leu), gnomAD X-50042390-A-C, REVEL 0.22, MetaLR 0.32
- M31K (p.Met31Lys), gnomAD X-50042391-T-A, REVEL 0.30, MetaLR 0.52
- M31I (p.Met31Ile), gnomAD X-50042392-G-T, REVEL 0.27, MetaLR 0.43
- D32G (p.Asp32Gly), rs202230774, ClinGen CA10413680, ClinVar RCV003956659, ESP rs202230774, REVEL 0.38, MetaLR 0.58, Benign, CLCN5-related disorder
- D32T (p.Asp32Thr), gnomAD X-50042391-TG-T, CADD 24.90
- D32N (p.Asp32Asn), gnomAD X-50042393-G-A, REVEL 0.33, MetaLR 0.51
- D32E (p.Asp32Glu), gnomAD X-50042395-C-A, REVEL 0.20, MetaLR 0.35
- D32D (p.Asp32Asp), gnomAD X-50042395-C-T, CADD 8.90
- I33V (p.Ile33Val), Ensembl rs1932255011, REVEL 0.27, MetaLR 0.46
- I33T (p.Ile33Thr), gnomAD X-50042397-T-C, REVEL 0.38, MetaLR 0.44
- I33I (p.Ile33Ile), gnomAD X-50042398-T-C, CADD 7.29
- I33M (p.Ile33Met), gnomAD X-50042398-T-G, REVEL 0.42, MetaLR 0.58
- P34L (p.Pro34Leu), cosmic curated COSV10654, REVEL 0.18, MetaLR 0.51
- P34T (p.Pro34Thr), Ensembl rs1932255194, REVEL 0.11, MetaLR 0.37
- P34Q (p.Pro34Gln), gnomAD X-50042398-TC-T, CADD 23.10
- P34P (p.Pro34Pro), gnomAD X-50042401-A-G, CADD 6.23
- A35G (p.Ala35Gly), gnomAD rs1557187288, REVEL 0.20, MetaLR 0.34
- A35S (p.Ala35Ser), gnomAD X-50042402-G-T, REVEL 0.26, MetaLR 0.44
- A35T (p.Ala35Thr), gnomAD X-50042402-G-A, REVEL 0.25, MetaLR 0.50
- A35A (p.Ala35Ala), rs1206185911, gnomAD X-50042404-A-G, CADD 3.98
- T36S (p.Thr36Ser), gnomAD X-50042405-A-T, REVEL 0.24, MetaLR 0.34
- T36A (p.Thr36Ala), gnomAD X-50042405-A-G, REVEL 0.29, MetaLR 0.33
- T36I (p.Thr36Ile), gnomAD X-50042406-C-T, REVEL 0.23, MetaLR 0.55
- T36T (p.Thr36Thr), gnomAD X-50042407-C-A, CADD 2.46
- A37T (p.Ala37Thr), cosmic curated COSV10442, gnomAD rs1557187293, REVEL 0.18, MetaLR 0.38
- A37S (p.Ala37Ser), gnomAD X-50042408-G-T, REVEL 0.22, MetaLR 0.32
- A37D (p.Ala37Asp), gnomAD X-50042409-C-A, REVEL 0.35, MetaLR 0.50
- A37A (p.Ala37Ala), rs1557187294, gnomAD X-50042410-T-C, CADD 8.38
- M38T (p.Met38Thr), TOPMed rs1264016265, gnomAD rs1264016265, REVEL 0.26, MetaLR 0.50
- M38V (p.Met38Val), gnomAD rs1557187297, REVEL 0.17, MetaLR 0.40
- M38I (p.Met38Ile), gnomAD X-50042413-G-A, REVEL 0.31, MetaLR 0.52
- D39G (p.Asp39Gly), 1000Genomes rs782364195, ExAC rs782364195, gnomAD rs782364195, REVEL 0.52, MetaLR 0.80
- D39N (p.Asp39Asn), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- D39I (p.Asp39Ile), gnomAD X-50042412-TG-T, CADD 25.00
- D39Y (p.Asp39Tyr), gnomAD X-50042414-G-T, REVEL 0.64, MetaLR 0.82
- D39D (p.Asp39Asp), gnomAD X-50042416-T-C, CADD 9.23
- F40L (p.Phe40Leu), NCI-TCGA TCGA novel, REVEL 0.31, MetaLR 0.43, Variant assessed as somatic; moderate impact.
- F40F (p.Phe40Phe), rs782515109, gnomAD X-50042419-C-T, CADD 11.40
- p.Ser41 Pro48del, gnomAD X-50042418-TCTCCA, CADD 17.80
- S41Y (p.Ser41Tyr), gnomAD X-50042421-C-A, REVEL 0.45, MetaLR 0.66
- S41S (p.Ser41Ser), gnomAD X-50042422-C-T, CADD 10.70
- M42L (p.Met42Leu), cosmic curated COSV65800, REVEL 0.21, MetaLR 0.48
- M42V (p.Met42Val), gnomAD X-50042423-A-G, REVEL 0.21, MetaLR 0.50
- M42T (p.Met42Thr), gnomAD X-50042424-T-C, REVEL 0.24, MetaLR 0.45
- R43K (p.Arg43Lys), TOPMed rs1335063795, REVEL 0.21, MetaLR 0.46
- R43G (p.Arg43Gly), gnomAD X-50042426-A-G, REVEL 0.21, MetaLR 0.54
- R43R (p.Arg43Arg), gnomAD X-50042428-A-G, CADD 13.00
- D44G (p.Asp44Gly), TOPMed rs1932257261, REVEL 0.43, MetaLR 0.65
- D44N (p.Asp44Asn), gnomAD rs1557187306, REVEL 0.40, MetaLR 0.58
- D44Y (p.Asp44Tyr), gnomAD X-50042429-G-T, REVEL 0.53, MetaLR 0.82
- D44V (p.Asp44Val), gnomAD X-50042430-A-T, REVEL 0.53, MetaLR 0.74
- D45Y (p.Asp45Tyr), TOPMed rs1932257432, REVEL 0.63, MetaLR 0.85
- D45N (p.Asp45Asn), gnomAD X-50042432-G-A, REVEL 0.45, MetaLR 0.81
- D45G (p.Asp45Gly), gnomAD X-50042433-A-G, REVEL 0.49, MetaLR 0.81
- D45E (p.Asp45Glu), gnomAD X-50042434-T-A, REVEL 0.37, MetaLR 0.73
- V46A (p.Val46Ala), gnomAD X-50042436-T-C, REVEL 0.30, MetaLR 0.41
- V46G (p.Val46Gly), gnomAD X-50042436-T-G, REVEL 0.28, MetaLR 0.46
- V46V (p.Val46Val), rs1557187308, gnomAD X-50042437-T-C, CADD 9.78
- P47H (p.Pro47His), TOPMed rs1277118243, REVEL 0.50, MetaLR 0.79
- P47S (p.Pro47Ser), cosmic curated COSV65802, REVEL 0.41, MetaLR 0.75
- P47T (p.Pro47Thr), gnomAD X-50042438-C-A, REVEL 0.45, MetaLR 0.77
- P47L (p.Pro47Leu), gnomAD X-50042439-C-T, REVEL 0.49, MetaLR 0.79
- P47P (p.Pro47Pro), gnomAD X-50042440-T-C, CADD 11.60
- P48L (p.Pro48Leu), cosmic curated COSV10442
- P48S (p.Pro48Ser), ESP rs375788993, ExAC rs375788993, TOPMed rs375788993, gnomAD rs375788993, REVEL 0.44, MetaLR 0.76
- P48T (p.Pro48Thr), gnomAD X-50042441-C-A, REVEL 0.46, MetaLR 0.78
Public CLCN5 analysis runs
- CLCN5 analysis run — CLCN5 (976 variants) — completed 2026-08-20