LEP (Leptin) variants and mutations
LEP (also known as Leptin) is a human protein-coding gene encoding a leptin protein. It signals nutritional energy stores to the hypothalamus and suppresses appetite while supporting normal endocrine and immune function. Biallelic loss-of-function variants cause severe early-onset obesity with hyperphagia and can impair pubertal development and immunity. This analysis covers 356 LEP variants and mutations. Of these, 82% have computational variant effect predictions. Disease context includes obesity due to congenital leptin deficiency, type 2 diabetes mellitus, and spondylolisthesis. Example LEP variants include H2R, H2H, and W3C.
Variant analysis overview
- Gene: LEP
- Protein: Leptin
- UniProt accession: P41159
- Organism: Homo sapiens
- Variants analyzed: 356
- Variant scope: all variants
- Completed: 2026-08-21
Variant and mutation evidence
- Variant composition: 168 unspecified-consequence records; 65 missense variants; 102 synonymous variants; 8 stop-gained variants; 7 frameshift variants; 1 in-frame deletions; 1 splice-region variants; 1 stop lost; 5 substitution
- Prediction scores: 291 variants have prediction scores (82% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: obesity due to congenital leptin deficiency, type 2 diabetes mellitus, spondylolisthesis, gastric ulcer, eye disorder, peptic ulcer disease, duodenal ulcer, obesity due to melanocortin 4 receptor deficiency, obesity disorder, Obesity, metabolic syndrome, polycystic ovary syndrome.
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 LEP variants
Examples include H2R, H2H, W3C, W3R, W3*, G4*, G4G, T5N. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- H2R (p.His2Arg), gnomAD 7-128252023-A-G, REVEL 0.04, CADD 0.03
- H2H (p.His2His), rs199879263, gnomAD 7-128252024-T-C, CADD 0.29
- W3C (p.Trp3Cys), NCI-TCGA Cosmic COSV1004, REVEL 0.11, CADD 0.32, Variant assessed as somatic; moderate impact.
- W3R (p.Trp3Arg), TOPMed rs1795280582
- W3* (p.Trp3Ter), gnomAD 7-128252027-G-A, CADD 27.10
- G4* (p.Gly4Ter), gnomAD 7-128252028-G-T, CADD 33.00
- G4G (p.Gly4Gly), gnomAD 7-128252030-A-G, CADD 6.23
- T5N (p.Thr5Asn), gnomAD 7-128252032-C-A, REVEL 0.09, CADD 0.05
- T5T (p.Thr5Thr), rs142904532, gnomAD 7-128252033-C-G, CADD 0.25
- L6M (p.Leu6Met), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- L6C (p.Leu6Cys), gnomAD 7-128252031-AC-A, CADD 6.98
- L6L (p.Leu6Leu), gnomAD 7-128252034-C-T, CADD 2.70
- C7G (p.Cys7Gly), gnomAD 7-128252037-T-G, REVEL 0.42, CADD 22.40
- C7C (p.Cys7Cys), rs201523305, gnomAD 7-128252039-C-T, CADD 0.57
- C7* (p.Cys7Ter), gnomAD 7-128252039-C-A, CADD 22.70
- G8R (p.Gly8Arg), rs200092598, ClinGen CA4469618, NCI-TCGA Cosmic COSV5824, ClinVar RCV003419235, REVEL 0.14, CADD 2.67, Uncertain significance, LEP-related disorder
- G8V (p.Gly8Val), TOPMed rs1562931888
- F9L (p.Phe9Leu), rs1401846669, NCI-TCGA Cosmic COSV5824, TOPMed rs1401846669, gnomAD rs1401846669, REVEL 0.04, CADD 4.94, Variant assessed as somatic; moderate impact.
- F9F (p.Phe9Phe), gnomAD 7-128252045-C-T, CADD 2.79
- L10F (p.Leu10Phe), rs775874401, ClinGen CA4469620, ClinVar RCV001919322, ClinVar RCV003401898, REVEL 0.35, CADD 22.50, Uncertain significance, not provided; LEP-related disorder
- L10L (p.Leu10Leu), rs770122731, gnomAD 7-128252046-T-C, CADD 4.62
- W11* (p.Trp11Ter), Ensembl rs1584606409, CADD 36.00
- W11G (p.Trp11Gly), gnomAD 7-128252049-T-G, REVEL 0.43, CADD 22.00
- L12I (p.Leu12Ile), rs767150017, NCI-TCGA Cosmic COSV5824, ExAC rs767150017, gnomAD rs767150017, REVEL 0.26, CADD 19.70, Variant assessed as somatic; moderate impact.
- L12L (p.Leu12Leu), rs540732424, gnomAD 7-128252054-T-C, CADD 3.62
- W13L (p.Trp13Leu), Ensembl rs76529182
- P14L (p.Pro14Leu), TOPMed rs1036136017, gnomAD rs1036136017, REVEL 0.09, CADD 6.62
- P14P (p.Pro14Pro), gnomAD 7-128252060-C-G, CADD 3.54
- Y15C (p.Tyr15Cys), ExAC rs760165439, TOPMed rs760165439, gnomAD rs760165439, REVEL 0.12, CADD 0.17
- L16F (p.Leu16Phe), ExAC rs765869630, gnomAD rs765869630
- L16I (p.Leu16Ile), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- L16V (p.Leu16Val), ExAC rs765869630, gnomAD rs765869630, REVEL 0.34, CADD 15.20
- F17L (p.Phe17Leu), Ensembl rs201067336, REVEL 0.03, CADD 5.88
- F17S (p.Phe17Ser), gnomAD 7-128252064-CT-C, CADD 22.60
- F17F (p.Phe17Phe), gnomAD 7-128252069-C-T, CADD 1.82
- Y18C (p.Tyr18Cys), rs148407750, ClinGen CA4469626, ClinVar RCV001162247, ClinVar RCV001882513, REVEL 0.11, CADD 3.54, Conflicting interpretations, Obesity due to congenital leptin deficiency; not provided
- V19D (p.Val19Asp), gnomAD 7-128252074-T-A, REVEL 0.25, CADD 6.70
- V19V (p.Val19Val), gnomAD 7-128252075-C-A, CADD 0.26
- Q20E (p.Gln20Glu), ExAC rs200179130, gnomAD rs200179130, REVEL 0.09, CADD 5.31
- Q20Q (p.Gln20Gln), rs1013725733, gnomAD 7-128252078-A-G, CADD 1.56
- V22M (p.Val22Met), TOPMed rs1795281529
- V22V (p.Val22Val), gnomAD 7-128252084-G-A, CADD 7.35
- P23L (p.Pro23Leu), NCI-TCGA Cosmic COSV1004, Variant assessed as somatic; moderate impact.
- P23T (p.Pro23Thr), Ensembl rs2116222183
- P23P (p.Pro23Pro), rs1795281569, gnomAD 7-128252087-C-A, CADD 5.19
- I24V (p.Ile24Val), TOPMed rs1468170863
- I24I (p.Ile24Ile), rs1423130790, gnomAD 7-128252090-C-T, CADD 6.55
- Q25* (p.Gln25Ter), rs2116222206, ClinGen CA369446638, ClinVar RCV001387311, Ensembl rs2116222206, Pathogenic
- Q25R (p.Gln25Arg), gnomAD 7-128252092-A-G, REVEL 0.14, CADD 0.21
- Q25Q (p.Gln25Gln), rs13306517, gnomAD 7-128252093-A-G, CADD 2.00
- K26E (p.Lys26Glu), gnomAD rs1795281758, REVEL 0.32, CADD 21.40
- K26I (p.Lys26Ile), Ensembl rs866491839
- V27V (p.Val27Val), rs1795281839, gnomAD 7-128252099-C-G, CADD 5.34
- Q28Q (p.Gln28Gln), rs202007341, gnomAD 7-128252102-A-G, CADD 5.99
- D29G (p.Asp29Gly), TOPMed rs1304598562, gnomAD rs1304598562, REVEL 0.44, CADD 22.60
- D29D (p.Asp29Asp), gnomAD 7-128252105-T-C, CADD 10.20
- D30N (p.Asp30Asn), gnomAD 7-128252106-G-A, REVEL 0.57, CADD 27.00
- D30D (p.Asp30Asp), rs200176785, gnomAD 7-128252108-C-T, CADD 8.57
- T31S (p.Thr31Ser), TOPMed rs1795281972, REVEL 0.28, CADD 20.00
- T31T (p.Thr31Thr), gnomAD 7-128252111-C-T, CADD 11.20
- T33I (p.Thr33Ile), ExAC rs752496962, gnomAD rs752496962, REVEL 0.26, CADD 16.00
- T33N (p.Thr33Asn), ExAC rs752496962, gnomAD rs752496962, REVEL 0.37, CADD 20.60
- I35del (p.Ile35del), rs747703977, gnomAD 7-128252118-CTCA-, CADD 18.30
- I35I (p.Ile35Ile), gnomAD 7-128252123-C-A, CADD 10.60
- K36R (p.Lys36Arg), ESP rs111650508, ExAC rs111650508, TOPMed rs111650508, gnomAD rs111650508, REVEL 0.53, CADD 21.50, Uncertain significance, LEP-related disorder
- K36K (p.Lys36Lys), rs1316215370, gnomAD 7-128252126-G-A, CADD 8.69
- T37K (p.Thr37Lys), Ensembl rs1795282145
- T37S (p.Thr37Ser), gnomAD 7-128252127-A-T, REVEL 0.64, CADD 24.20
- I38T (p.Ile38Thr), Ensembl rs1795282176, REVEL 0.61, CADD 23.40
- I38V (p.Ile38Val), gnomAD 7-128252130-A-G, REVEL 0.41, CADD 22.50
- V39A (p.Val39Ala), gnomAD 7-128252134-T-C, REVEL 0.31, CADD 22.50
- V39V (p.Val39Val), gnomAD 7-128252135-C-T, CADD 5.91
- T40A (p.Thr40Ala), TOPMed rs1269678153
- T40I (p.Thr40Ile), gnomAD rs1342830248, REVEL 0.23, CADD 17.20, Uncertain significance, not provided
- R41K (p.Arg41Lys), Ensembl rs1795282327
- N43S (p.Asn43Ser), TOPMed rs201494642, REVEL 0.10, CADD 0.02
- N43T (p.Asn43Thr), TOPMed rs201494642
- N43N (p.Asn43Asn), rs777989230, gnomAD 7-128252147-T-C, CADD 2.72
- N43K (p.Asn43Lys), gnomAD 7-128252147-T-G, REVEL 0.19, CADD 16.00
- D44D (p.Asp44Asp), rs372064089, gnomAD 7-128252150-C-T, CADD 1.74
- I45N (p.Ile45Asn), ExAC rs781301976, gnomAD rs781301976, REVEL 0.57, CADD 24.30
- I45V (p.Ile45Val), rs145044661, ClinGen CA4469634, ClinVar RCV003969022, ESP rs145044661, REVEL 0.22, CADD 11.50, Uncertain significance, LEP-related disorder
- I45L (p.Ile45Leu), gnomAD 7-128252151-A-C, REVEL 0.15, CADD 9.06
- I45I (p.Ile45Ile), gnomAD 7-128252153-T-C, CADD 2.30
- I45M (p.Ile45Met), gnomAD 7-128252153-T-G, REVEL 0.36, CADD 13.30
- S46L (p.Ser46Leu), Ensembl rs866158426
- S46S (p.Ser46Ser), rs746345055, gnomAD 7-128252156-A-G, CADD 6.03
- H47Y (p.His47Tyr), gnomAD 7-128252157-C-T, REVEL 0.58, CADD 20.80
- H47Q (p.His47Gln), rs771590018, gnomAD 7-128252158-AC-A, CADD 17.60
- H47H (p.His47His), rs1795282687, gnomAD 7-128252159-C-T, CADD 1.84
- T48M (p.Thr48Met), rs770247453, ClinGen CA4469638, NCI-TCGA Cosmic COSV1004, ClinVar RCV001162248, REVEL 0.08, CADD 3.04, Uncertain significance, Obesity due to congenital leptin deficiency
- T48R (p.Thr48Arg), ExAC rs770247453, TOPMed rs770247453, gnomAD rs770247453, REVEL 0.11, CADD 0.75, Uncertain significance
- T48T (p.Thr48Thr), rs1800583, gnomAD 7-128252162-G-A, CADD 22.70
- Q49H (p.Gln49His), TOPMed rs1795310969
- Q49R (p.Gln49Arg), Ensembl rs1584607701
- S50S (p.Ser50Ser), gnomAD 7-128254409-A-T, CADD 0.34
- V51I (p.Val51Ile), TOPMed rs1287727753, REVEL 0.10, CADD 16.70
- V51P (p.Val51Pro), gnomAD 7-128254403-GCAGT, CADD 33.00
- V51A (p.Val51Ala), gnomAD 7-128254411-T-C, REVEL 0.50, CADD 23.40
- S52F (p.Ser52Phe), ExAC rs776443424, TOPMed rs776443424, gnomAD rs776443424, REVEL 0.56, CADD 23.60
- S52S (p.Ser52Ser), rs1221946497, gnomAD 7-128254415-C-T, CADD 6.65
- K54R (p.Lys54Arg), gnomAD 7-128254420-A-G, REVEL 0.17, CADD 6.34
- Q55E (p.Gln55Glu), ExAC rs759056593, gnomAD rs759056593, REVEL 0.34, CADD 15.80
- Q55K (p.Gln55Lys), ExAC rs759056593, gnomAD rs759056593, REVEL 0.38, CADD 16.10
- Q55* (p.Gln55Ter), gnomAD 7-128254422-C-T, CADD 36.00
- Q55H (p.Gln55His), gnomAD 7-128254424-G-T, REVEL 0.17, CADD 3.90
- Q55Q (p.Gln55Gln), rs138908051, gnomAD 7-128254424-G-A, CADD 0.87
- V57V (p.Val57Val), rs775557183, gnomAD 7-128254430-C-T, CADD 2.86
- T58S (p.Thr58Ser), Ensembl rs1795311284
- T58T (p.Thr58Thr), rs199647957, gnomAD 7-128254433-C-G, CADD 0.06
- G59S (p.Gly59Ser), rs200575914, ClinGen CA166745178, ClinVar RCV003313818, ClinVar RCV003318515, REVEL 0.55, CADD 23.80, Pathogenic, Obesity due to congenital leptin deficiency
- L60V (p.Leu60Val), gnomAD 7-128254437-T-G, REVEL 0.59, CADD 22.60
- L60W (p.Leu60Trp), gnomAD 7-128254438-T-G, REVEL 0.69, CADD 24.80
- L60L (p.Leu60Leu), rs1160357234, gnomAD 7-128254439-G-A, CADD 3.25
- D61N (p.Asp61Asn), rs886061972, ClinGen CA10623192, ClinVar RCV000376522, Ensembl rs886061972, AlphaMissense 0.27, MetaLR 0.61, Uncertain significance, Obesity due to congenital leptin deficiency
- F62L (p.Phe62Leu), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- I63L (p.Ile63Leu), ExAC rs751272426, TOPMed rs751272426, gnomAD rs751272426, REVEL 0.36, CADD 18.10
- P64S (p.Pro64Ser), rs2485445933, ClinGen CA369443667, ClinVar RCV003313819, ClinVar RCV003318516, Pathogenic, Obesity due to congenital leptin deficiency
- P64P (p.Pro64Pro), gnomAD 7-128254451-T-A, CADD 7.99
- G65R (p.Gly65Arg), NCI-TCGA Cosmic COSV1004, Variant assessed as somatic; moderate impact.
- G65V (p.Gly65Val), rs2485445952, ClinGen CA369443676, ClinVar RCV004264621, Uncertain significance, not specified
- G65G (p.Gly65Gly), rs761690570, gnomAD 7-128254454-G-T, CADD 0.78
- L66H (p.Leu66His), TOPMed rs1795311621, gnomAD rs1795311621, REVEL 0.40, CADD 17.10
- L66R (p.Leu66Arg), rs761170909, gnomAD 7-128254451-T-TGG, CADD 23.60
- H67P (p.His67Pro), Ensembl rs1584607746
- H67Y (p.His67Tyr), gnomAD 7-128254458-C-T, REVEL 0.14, CADD 4.27
- H67H (p.His67His), gnomAD 7-128254460-C-T, CADD 0.52
- P68A (p.Pro68Ala), gnomAD 7-128254461-C-G, REVEL 0.39, CADD 2.82
- P68P (p.Pro68Pro), rs140510728, gnomAD 7-128254463-C-T, CADD 0.16
- I69T (p.Ile69Thr), TOPMed rs1417571919, gnomAD rs1417571919, REVEL 0.13, CADD 0.54, Uncertain significance, LEP-related disorder
- I69V (p.Ile69Val), Ensembl rs1795311785
- T71N (p.Thr71Asn), rs886061973, ClinGen CA10628233, ClinVar RCV000346275, TOPMed rs886061973, REVEL 0.07, CADD 4.25, Uncertain significance, Obesity due to congenital leptin deficiency
- T71I (p.Thr71Ile), gnomAD 7-128254471-C-T, REVEL 0.18, CADD 16.60
- T71T (p.Thr71Thr), rs200187656, gnomAD 7-128254472-C-T, CADD 0.88
- S73S (p.Ser73Ser), gnomAD 7-128254478-C-A, CADD 2.47
- S73A (p.Ser73Ala), rs756180416, []
- K74M (p.Lys74Met), gnomAD 7-128254480-A-T, REVEL 0.12, CADD 13.00
- M75T (p.Met75Thr), gnomAD 7-128254483-T-C, REVEL 0.52, CADD 23.20
- M75R (p.Met75Arg), gnomAD 7-128254483-T-G, REVEL 0.58, CADD 23.70
- D76A (p.Asp76Ala), gnomAD rs1332916395
- D76G (p.Asp76Gly), gnomAD rs1332916395, REVEL 0.69, CADD 23.90
- D76V (p.Asp76Val), gnomAD rs1332916395, REVEL 0.65, CADD 23.80
- D76Y (p.Asp76Tyr), TOPMed rs200915360, gnomAD rs200915360, REVEL 0.65, CADD 22.90
- Q77R (p.Gln77Arg), gnomAD 7-128254489-A-G, REVEL 0.51, CADD 23.80
- Q77Q (p.Gln77Gln), gnomAD 7-128254490-G-A, CADD 3.33
- T78S (p.Thr78Ser), gnomAD 7-128254491-A-T, REVEL 0.52, CADD 22.30
- T78T (p.Thr78Thr), rs201665158, gnomAD 7-128254493-A-G, CADD 0.07
- A80S (p.Ala80Ser), ExAC rs756180416, gnomAD rs756180416, REVEL 0.39, CADD 18.20
- A80V (p.Ala80Val), ExAC rs780163329, gnomAD rs780163329, REVEL 0.19, CADD 7.33
- A80A (p.Ala80Ala), rs1381183438, gnomAD 7-128254499-A-G, CADD 0.61
- V81V (p.Val81Val), rs930810435, gnomAD 7-128254502-C-G, CADD 3.04
- Q83* (p.Gln83Ter), TOPMed rs1187329966, gnomAD rs1187329966, CADD 36.00
- Q83Q (p.Gln83Gln), rs754347841, gnomAD 7-128254508-A-G, CADD 3.54
- Q84* (p.Gln84Ter), ExAC rs755477612, CADD 35.00
- Q84K (p.Gln84Lys), gnomAD 7-128254509-C-A, REVEL 0.17, CADD 11.40
- I85F (p.Ile85Phe), gnomAD rs1311825614, REVEL 0.52, CADD 22.20
- I85V (p.Ile85Val), gnomAD 7-128254512-A-G, REVEL 0.11, CADD 8.65
- I85I (p.Ile85Ile), gnomAD 7-128254514-C-T, CADD 4.46
- L86F (p.Leu86Phe), ExAC rs748408158, gnomAD rs748408158, REVEL 0.65, CADD 16.90
- L86L (p.Leu86Leu), rs772575402, gnomAD 7-128254517-C-T, CADD 4.06
- S88C (p.Ser88Cys), TOPMed rs199838573, gnomAD rs199838573, REVEL 0.29, CADD 20.80
- S88I (p.Ser88Ile), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- S88T (p.Ser88Thr), Ensembl rs1795312760
- S88S (p.Ser88Ser), rs1203819487, gnomAD 7-128254523-T-C, CADD 0.54
- M89I (p.Met89Ile), NCI-TCGA Cosmic COSV1004, Variant assessed as somatic; moderate impact.
- M89V (p.Met89Val), gnomAD rs1231681476, REVEL 0.09, CADD 14.90
- P90A (p.Pro90Ala), ExAC rs780990529, gnomAD rs780990529
- P90R (p.Pro90Arg), TOPMed rs1206379074, gnomAD rs1206379074, REVEL 0.21, CADD 20.60
- P90T (p.Pro90Thr), ExAC rs780990529, gnomAD rs780990529, REVEL 0.12, CADD 14.20
- S91S (p.Ser91Ser), gnomAD 7-128254532-C-T, CADD 1.33
- R92G (p.Arg92Gly), ExAC rs745576625, TOPMed rs745576625, gnomAD rs745576625
- R92K (p.Arg92Lys), NCI-TCGA Cosmic COSV5824, Variant assessed as somatic; moderate impact.
- R92R (p.Arg92Arg), rs745576625, gnomAD 7-128254533-A-C, CADD 1.97
- N93N (p.Asn93Asn), rs774906243, gnomAD 7-128254538-C-T, CADD 0.02
- V94L (p.Val94Leu), 1000Genomes rs17151919, ESP rs17151919, ExAC rs17151919, TOPMed rs17151919, Benign
- V94M (p.Val94Met), rs17151919, ClinGen CA4469685, ClinVar RCV000445399, ClinVar RCV000947067, REVEL 0.17, CADD 0.89, Benign/Likely benign, Monogenic diabetes; not provided
- V94A (p.Val94Ala), gnomAD 7-128254540-T-C, REVEL 0.13, CADD 14.80
- V94V (p.Val94Val), rs768428766, gnomAD 7-128254541-G-A, CADD 1.01
- I95N (p.Ile95Asn), gnomAD rs1226851396, REVEL 0.21, CADD 22.60
- I95I (p.Ile95Ile), rs200061184, gnomAD 7-128254544-C-T, CADD 6.37
Public LEP analysis runs
- LEP analysis run — LEP (356 variants) — completed 2026-08-21