G6PC2 (Glucose-6-phosphatase 2) variants and mutations
G6PC2 (also known as Glucose-6-phosphatase 2) is a human protein-coding gene encoding a glucose-6-phosphatase 2 protein. It modulates the glucose sensitivity of pancreatic beta cells by hydrolyzing glucose-6-phosphate within the endoplasmic reticulum. Common variants strongly influence fasting glucose levels without necessarily causing diabetes, reflecting a role in setting the beta-cell glucose threshold. This analysis covers 770 G6PC2 variants and mutations. Of these, 85% have computational variant effect predictions. Disease context includes glucose metabolism disease, gestational diabetes, and inborn carbohydrate metabolic disorder. Example G6PC2 variants include D2N, D2G, and F3S.
Variant analysis overview
- Gene: G6PC2
- Protein: Glucose-6-phosphatase 2
- UniProt accession: Q9NQR9
- Organism: Homo sapiens
- Variants analyzed: 770
- Variant scope: all variants
- Completed: 2026-08-22
Variant and mutation evidence
- Variant composition: 459 unspecified-consequence records; 173 missense variants; 89 synonymous variants; 12 stop-gained variants; 28 frameshift variants; 4 in-frame deletions; 4 splice-region variants; 1 substitution
- Prediction scores: 656 variants have prediction scores (85% of the analyzed set).
Clinical, disease, and population context
- Disease context: 25 disease associations are represented. Top associations: glucose metabolism disease, gestational diabetes, inborn carbohydrate metabolic disorder, Abnormal glucose homeostasis, intestinal disaccharidase deficiency, metabolic syndrome, type 2 diabetes mellitus, coronary artery calcification, Abnormality of the skeletal system, diabetic retinopathy, diabetic eye disease, Hypercholesterolemia.
Protein structure and variant hotspots
- Protein features: 9 transmembrane segments; 2 binding sites; 1 post-translational modification sites.
- Structural context: 345 variants have structural context.
- PTM context: 1 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, AlphaFold DB, gnomAD constraint, Open Targets, MaveDB, LitVar.
Notable G6PC2 variants
Examples include D2N, D2G, F3S, F3L, L4F, L4I, L4L, H5D. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.
- D2N (p.Asp2Asn), TOPMed rs1690585208
- D2G (p.Asp2Gly), gnomAD 2-168901336-A-G, REVEL 0.71, CADD 24.20
- F3S (p.Phe3Ser), gnomAD rs1480492278, REVEL 0.31, CADD 22.70
- F3L (p.Phe3Leu), gnomAD 2-168901338-T-C, REVEL 0.21, CADD 18.40
- L4F (p.Leu4Phe), TOPMed rs1385272675, gnomAD rs1385272675, REVEL 0.25, CADD 22.20
- L4I (p.Leu4Ile), gnomAD 2-168901341-C-A, REVEL 0.23, CADD 17.80
- L4L (p.Leu4Leu), gnomAD 2-168901343-T-C, CADD 11.10
- H5D (p.His5Asp), TOPMed rs1370237922, gnomAD rs1370237922, REVEL 0.72, CADD 25.20
- H5Q (p.His5Gln), NCI-TCGA Cosmic COSV9996, cosmic curated COSV99960, Ensembl rs1690585460, REVEL 0.43, CADD 14.40, Variant assessed as somatic; moderate impact.
- H5N (p.His5Asn), gnomAD 2-168901344-C-A, REVEL 0.63, CADD 24.80
- H5Y (p.His5Tyr), gnomAD 2-168901344-C-T, REVEL 0.62, CADD 23.50
- H5H (p.His5His), gnomAD 2-168901346-C-T, CADD 6.44
- R6G (p.Arg6Gly), gnomAD 2-168901347-A-G, REVEL 0.25, CADD 20.60
- R6M (p.Arg6Met), gnomAD 2-168901348-G-T, REVEL 0.28, CADD 23.20
- R6K (p.Arg6Lys), gnomAD 2-168901348-G-A, REVEL 0.30, CADD 20.10
- R6S (p.Arg6Ser), gnomAD 2-168901349-G-C, REVEL 0.21, CADD 12.80
- N7D (p.Asn7Asp), rs1690585528, ClinGen CA349107838, ClinVar RCV004148078, TOPMed rs1690585528, AlphaMissense 0.09, MetaLR 0.59, Uncertain significance, not specified
- N7T (p.Asn7Thr), gnomAD rs1690585591, REVEL 0.14, CADD 17.10
- N7S (p.Asn7Ser), gnomAD 2-168901351-A-G, REVEL 0.13, CADD 15.80
- N7N (p.Asn7Asn), rs757904389, gnomAD 2-168901352-T-C, CADD 8.62
- N7K (p.Asn7Lys), gnomAD 2-168901352-T-A, REVEL 0.20, CADD 16.20
- G8E (p.Gly8Glu), ESP rs368382511, TOPMed rs368382511, gnomAD rs368382511, REVEL 0.41, CADD 21.10
- G8V (p.Gly8Val), ESP rs368382511, TOPMed rs368382511, gnomAD rs368382511
- G8G (p.Gly8Gly), rs1690585820, gnomAD 2-168901355-A-G, CADD 10.50
- V9M (p.Val9Met), Ensembl rs1419369620
- V9G (p.Val9Gly), gnomAD 2-168901357-T-G, REVEL 0.93, CADD 27.40
- V9V (p.Val9Val), gnomAD 2-168901358-G-A, CADD 7.48
- L10P (p.Leu10Pro), TOPMed rs1690586037, REVEL 0.58, CADD 23.80
- L10I (p.Leu10Ile), gnomAD 2-168901359-C-A, REVEL 0.24, CADD 19.10
- L10L (p.Leu10Leu), rs779614984, gnomAD 2-168901361-C-T, CADD 2.45
- I12T (p.Ile12Thr), gnomAD 2-168901366-T-C, REVEL 0.34, CADD 18.30
- Q13K (p.Gln13Lys), gnomAD 2-168901368-C-A, REVEL 0.41, CADD 20.90
- Q13* (p.Gln13Ter), gnomAD 2-168901368-C-T, CADD 36.00
- Q13R (p.Gln13Arg), gnomAD 2-168901369-A-G, REVEL 0.45, CADD 20.90
- Q13Q (p.Gln13Gln), gnomAD 2-168901370-G-A, CADD 7.57
- H14N (p.His14Asn), rs746671578, ExAC rs746671578, gnomAD rs746671578, REVEL 0.18, CADD 19.40, Variant assessed as somatic; moderate impact.
- H14P (p.His14Pro), ExAC rs781044423, gnomAD rs781044423
- H14Y (p.His14Tyr), ExAC rs746671578, gnomAD rs746671578, REVEL 0.16, CADD 11.60
- H14S (p.His14Ser), gnomAD 2-168901369-A-AGA, CADD 26.40
- L15M (p.Leu15Met), ExAC rs747911600, gnomAD rs747911600, REVEL 0.70, CADD 24.40
- L15A (p.Leu15Ala), gnomAD 2-168901372-ATT-A, CADD 24.80
- L15F (p.Leu15Phe), gnomAD 2-168901376-G-T, REVEL 0.72, CADD 23.50
- Q16H (p.Gln16His), 1000Genomes rs372008743, ESP rs372008743, ExAC rs372008743, TOPMed rs372008743, REVEL 0.78, CADD 23.80
- Q16R (p.Gln16Arg), ExAC rs769873771, TOPMed rs769873771, gnomAD rs769873771, REVEL 0.89, CADD 25.70
- Q16K (p.Gln16Lys), gnomAD 2-168901377-C-A, REVEL 0.77, CADD 24.10
- K17T (p.Lys17Thr), TOPMed rs1690587025
- K17del (p.Lys17del), rs768169038, gnomAD 2-168901377-CAGA-, CADD 18.90
- K17K (p.Lys17Lys), rs745981571, gnomAD 2-168901382-G-A, CADD 6.16
- D18E (p.Asp18Glu), TOPMed rs759777262, REVEL 0.25, CADD 14.80
- D18Y (p.Asp18Tyr), ExAC rs772185727, gnomAD rs772185727
- Y19C (p.Tyr19Cys), gnomAD rs1215685943, REVEL 0.60, CADD 25.50
- Y19Y (p.Tyr19Tyr), gnomAD 2-168901388-C-T, CADD 2.52
- R20* (p.Arg20Ter), gnomAD rs1275647193, CADD 34.00
- R20P (p.Arg20Pro), ESP rs143670077, ExAC rs143670077, TOPMed rs143670077, gnomAD rs143670077, REVEL 0.22, CADD 17.90
- R20Q (p.Arg20Gln), rs143670077, cosmic curated COSV56373, ESP rs143670077, ExAC rs143670077, REVEL 0.09, CADD 14.30, Variant assessed as somatic; moderate impact.
- R20R (p.Arg20Arg), gnomAD 2-168901389-C-A, CADD 8.15
- A21D (p.Ala21Asp), Ensembl rs1690587997, REVEL 0.18, CADD 14.40
- A21T (p.Ala21Thr), 1000Genomes rs577033273, REVEL 0.11, CADD 15.80
- Y22C (p.Tyr22Cys), TOPMed rs1690588216, REVEL 0.25, CADD 18.20
- Y22H (p.Tyr22His), Ensembl rs1574373122
- Y23H (p.Tyr23His), gnomAD rs1690588311, REVEL 0.18, CADD 19.70
- Y23* (p.Tyr23Ter), gnomAD 2-168901400-C-G, CADD 25.40
- T24P (p.Thr24Pro), gnomAD rs1204827592, REVEL 0.14, CADD 19.20
- T24S (p.Thr24Ser), gnomAD rs1204827592, REVEL 0.14, CADD 11.80
- T24A (p.Thr24Ala), gnomAD 2-168901401-A-G, REVEL 0.15, CADD 14.70
- T24N (p.Thr24Asn), gnomAD 2-168901402-C-A, REVEL 0.17, CADD 0.49
- T24T (p.Thr24Thr), gnomAD 2-168901403-T-C, CADD 9.16
- F25F (p.Phe25Phe), rs951547571, gnomAD 2-168901406-T-C, CADD 10.70
- L26V (p.Leu26Val), gnomAD rs510399
- L26* (p.Leu26Ter), rs1270007918, gnomAD 2-168901402-CT-C, CADD 23.50
- L26L (p.Leu26Leu), rs510399, gnomAD 2-168901407-C-T, CADD 8.98
- N27K (p.Asn27Lys), NCI-TCGA Cosmic COSV5637, cosmic curated COSV56371, Variant assessed as somatic; moderate impact.
- N27S (p.Asn27Ser), 1000Genomes rs546055009, ExAC rs546055009, gnomAD rs546055009, REVEL 0.13, CADD 15.90
- N27N (p.Asn27Asn), gnomAD 2-168901412-T-C, CADD 7.37
- F28C (p.Phe28Cys), NCI-TCGA Cosmic COSV5637, cosmic curated COSV56372, Variant assessed as somatic; moderate impact.
- F28L (p.Phe28Leu), NCI-TCGA Cosmic COSV5637, cosmic curated COSV56373, REVEL 0.44, CADD 20.30, Variant assessed as somatic; moderate impact.
- F28V (p.Phe28Val), ExAC rs34725343, TOPMed rs34725343, gnomAD rs34725343, REVEL 0.60, CADD 23.70
- M29V (p.Met29Val), gnomAD 2-168901416-A-G, REVEL 0.18, CADD 11.40
- M29I (p.Met29Ile), gnomAD 2-168901418-G-A, REVEL 0.19, CADD 13.40
- S30F (p.Ser30Phe), cosmic curated COSV10608, ESP rs142189264, ExAC rs142189264, TOPMed rs142189264, REVEL 0.81, CADD 24.40
- S30T (p.Ser30Thr), TOPMed rs1174966402
- S30Y (p.Ser30Tyr), gnomAD 2-168901420-C-A, REVEL 0.83, CADD 24.00
- S30S (p.Ser30Ser), gnomAD 2-168901421-C-A, CADD 5.54
- N31D (p.Asn31Asp), Ensembl rs1690589638, REVEL 0.23, CADD 16.60
- N31H (p.Asn31His), Ensembl rs1690589638
- N31I (p.Asn31Ile), cosmic curated COSV56373, ESP rs375350062, ExAC rs375350062, gnomAD rs375350062, REVEL 0.16, CADD 8.98
- N31S (p.Asn31Ser), ESP rs375350062, ExAC rs375350062, gnomAD rs375350062, cosmic curated COSV10727, REVEL 0.14, CADD 5.31
- N31N (p.Asn31Asn), rs1690589802, gnomAD 2-168901424-T-C, CADD 6.76
- V32I (p.Val32Ile), gnomAD 2-168901425-G-A, REVEL 0.22, CADD 16.00
- G33R (p.Gly33Arg), TOPMed rs1199887137, gnomAD rs1199887137, REVEL 0.85, CADD 26.30
- G33V (p.Gly33Val), NCI-TCGA Cosmic COSV5637, cosmic curated COSV56371, Variant assessed as somatic; moderate impact.
- G33G (p.Gly33Gly), gnomAD 2-168901430-A-G, CADD 7.80
- D34G (p.Asp34Gly), gnomAD rs1427715902
- D34N (p.Asp34Asn), gnomAD 2-168901431-G-A, REVEL 0.57, CADD 23.20
- D34E (p.Asp34Glu), gnomAD 2-168901433-C-A, REVEL 0.40, CADD 14.70
- P35Q (p.Pro35Gln), rs776242682, gnomAD 2-168901432-ACC-A, CADD 25.00
- P35S (p.Pro35Ser), gnomAD 2-168901434-C-T, REVEL 0.53, CADD 22.90
- P35A (p.Pro35Ala), gnomAD 2-168901434-C-G, REVEL 0.46, CADD 22.20
- P35R (p.Pro35Arg), gnomAD 2-168901435-C-G, REVEL 0.54, CADD 22.60
- P35P (p.Pro35Pro), gnomAD 2-168901436-C-G, CADD 8.04
- R36K (p.Arg36Lys), gnomAD rs1365959497, REVEL 0.27, CADD 17.70
- R36M (p.Arg36Met), NCI-TCGA Cosmic COSV5637, cosmic curated COSV56373, Variant assessed as somatic; moderate impact.
- R36R (p.Arg36Arg), rs762439205, gnomAD 2-168901437-A-C, CADD 9.36
- N37S (p.Asn37Ser), ExAC rs777162017, gnomAD rs777162017, REVEL 0.40, CADD 22.80
- N37I (p.Asn37Ile), gnomAD 2-168901439-GA-G, CADD 25.60
- I38L (p.Ile38Leu), ESP rs149874491, ExAC rs149874491, TOPMed rs149874491, gnomAD rs149874491, REVEL 0.26, CADD 22.60
- I38T (p.Ile38Thr), Ensembl rs1249599611, REVEL 0.15, CADD 15.40
- I38N (p.Ile38Asn), gnomAD 2-168901444-T-A, REVEL 0.51, CADD 22.90
- I38I (p.Ile38Ile), rs1228200574, gnomAD 2-168901445-C-A, CADD 5.38
- I38M (p.Ile38Met), gnomAD 2-168901445-C-G, REVEL 0.34, CADD 15.80
- F39C (p.Phe39Cys), Ensembl rs2105849349
- F39V (p.Phe39Val), gnomAD rs1272455884, REVEL 0.90, CADD 26.20
- F39L (p.Phe39Leu), gnomAD 2-168901446-T-C, REVEL 0.86, CADD 27.20
- F39Y (p.Phe39Tyr), gnomAD 2-168901447-T-A, REVEL 0.71, CADD 25.90
- F40C (p.Phe40Cys), ExAC rs780943361, TOPMed rs780943361, gnomAD rs780943361, REVEL 0.24, CADD 21.20
- F40S (p.Phe40Ser), ExAC rs780943361, TOPMed rs780943361, gnomAD rs780943361, REVEL 0.18, CADD 16.90
- F40F (p.Phe40Phe), rs1228304055, gnomAD 2-168901451-C-T, CADD 7.49
- I41N (p.Ile41Asn), NCI-TCGA Cosmic COSV9996, cosmic curated COSV99960, Variant assessed as somatic; moderate impact.
- I41T (p.Ile41Thr), gnomAD 2-168901453-T-C, REVEL 0.56, CADD 23.30
- I41I (p.Ile41Ile), rs752584958, gnomAD 2-168901454-T-C, CADD 10.60
- Y42C (p.Tyr42Cys), TOPMed rs1690590909
- Y42Y (p.Tyr42Tyr), gnomAD 2-168901457-T-C, CADD 7.02
- F43C (p.Phe43Cys), gnomAD rs1361961688, cosmic curated COSV10727, REVEL 0.87, CADD 27.20
- F43F (p.Phe43Phe), gnomAD 2-168901460-T-C, CADD 9.98
- P44S (p.Pro44Ser), NCI-TCGA Cosmic COSV5637, cosmic curated COSV56371, Variant assessed as somatic; moderate impact.
- P44T (p.Pro44Thr), gnomAD 2-168901461-C-A, REVEL 0.92, CADD 24.50
- L45F (p.Leu45Phe), gnomAD 2-168901464-C-T, REVEL 0.20, CADD 21.80
- L45I (p.Leu45Ile), gnomAD 2-168901464-C-A, REVEL 0.10, CADD 12.70
- C46R (p.Cys46Arg), TOPMed rs1690591180
- C46W (p.Cys46Trp), Ensembl rs2105849387
- C46Y (p.Cys46Tyr), Ensembl rs753657066, REVEL 0.41, CADD 23.70
- C46F (p.Cys46Phe), rs761436513, gnomAD 2-168901464-CTT-C, CADD 26.80
- Q48H (p.Gln48His), ExAC rs755938672, TOPMed rs755938672, gnomAD rs755938672
- Q48L (p.Gln48Leu), NCI-TCGA TCGA novel, Variant assessed as somatic; moderate impact.
- Q48Q (p.Gln48Gln), rs755938672, gnomAD 2-168901475-A-G, CADD 6.85
- F49C (p.Phe49Cys), NCI-TCGA Cosmic COSV5637, cosmic curated COSV56372, REVEL 0.31, CADD 24.10, Variant assessed as somatic; moderate impact.
- F49L (p.Phe49Leu), gnomAD 2-168901476-T-C, REVEL 0.12, CADD 13.90
- N50S (p.Asn50Ser), TOPMed rs1690591451, REVEL 0.30, CADD 17.80
- N50Y (p.Asn50Tyr), gnomAD 2-168901479-A-T, REVEL 0.40, CADD 23.60
- N50I (p.Asn50Ile), gnomAD 2-168901480-A-T, REVEL 0.49, CADD 23.80
- Q51H (p.Gln51His), NCI-TCGA Cosmic COSV9996, cosmic curated COSV99960, REVEL 0.13, CADD 18.00, Variant assessed as somatic; moderate impact.
- Q51R (p.Gln51Arg), ExAC rs777921361, gnomAD rs777921361, REVEL 0.14, CADD 18.40
- Q51K (p.Gln51Lys), gnomAD 2-168901482-C-A, REVEL 0.19, CADD 19.10
- Q51Q (p.Gln51Gln), gnomAD 2-168901484-G-A, CADD 7.63
- T52I (p.Thr52Ile), ESP rs371294159, ExAC rs371294159, TOPMed rs371294159, gnomAD rs371294159, REVEL 0.17, CADD 16.00
- T52K (p.Thr52Lys), ESP rs371294159, ExAC rs371294159, TOPMed rs371294159, gnomAD rs371294159, REVEL 0.21, CADD 15.10
- T52A (p.Thr52Ala), gnomAD 2-168901485-A-G, REVEL 0.17, CADD 15.00
- T52R (p.Thr52Arg), gnomAD 2-168901486-C-G, REVEL 0.22, CADD 15.20
- T52T (p.Thr52Thr), rs1043751558, gnomAD 2-168901487-A-T, CADD 9.37
- V53A (p.Val53Ala), rs868267884, ClinGen CA59845688, ClinVar RCV004151200, Ensembl rs868267884, REVEL 0.38, CADD 22.50, Uncertain significance, not specified
- V53I (p.Val53Ile), ESP rs375874967, ExAC rs375874967, TOPMed rs375874967, gnomAD rs375874967, REVEL 0.30, CADD 21.80
- V53V (p.Val53Val), gnomAD 2-168901490-T-C, CADD 10.50
- G54E (p.Gly54Glu), gnomAD rs1447656406, REVEL 0.84, CADD 26.00
- G54R (p.Gly54Arg), gnomAD 2-168901491-G-A, REVEL 0.90, CADD 28.80
- G54G (p.Gly54Gly), gnomAD 2-168901493-A-G, CADD 11.00
- T55A (p.Thr55Ala), Ensembl rs1690591994, REVEL 0.43, CADD 23.70
- T55N (p.Thr55Asn), gnomAD 2-168901495-C-A, REVEL 0.52, CADD 23.90
- T55T (p.Thr55Thr), gnomAD 2-168901496-C-A, CADD 7.83
- K56R (p.Lys56Arg), gnomAD rs1167870453, REVEL 0.26, CADD 22.00
- K56K (p.Lys56Lys), rs1457837048, gnomAD 2-168901499-G-A, CADD 10.20
- M57I (p.Met57Ile), NCI-TCGA Cosmic COSV5637, Variant assessed as somatic; moderate impact.
- M57T (p.Met57Thr), Ensembl rs2105849456, REVEL 0.43, CADD 23.20
- I58L (p.Ile58Leu), Ensembl rs1690592225, REVEL 0.33, CADD 22.90
- I58M (p.Ile58Met), ExAC rs780190171, gnomAD rs780190171, REVEL 0.52, CADD 22.00, Uncertain significance, not specified
- I58T (p.Ile58Thr), TOPMed rs1228183177, REVEL 0.89, CADD 26.10
- I58I (p.Ile58Ile), rs780190171, gnomAD 2-168901505-A-T, CADD 9.11
- W59* (p.Trp59Ter), NCI-TCGA TCGA novel, CADD 39.00, Variant assessed as somatic; high impact.
- W59L (p.Trp59Leu), NCI-TCGA TCGA novel, REVEL 0.64, CADD 27.50, Variant assessed as somatic; moderate impact.
- W59R (p.Trp59Arg), rs369755574, ESP rs369755574, TOPMed rs369755574, gnomAD rs369755574, REVEL 0.63, CADD 23.20, Variant assessed as somatic; moderate impact.
- W59C (p.Trp59Cys), gnomAD 2-168901508-G-T, REVEL 0.80, CADD 29.30
- V60A (p.Val60Ala), TOPMed rs1349005668, gnomAD rs1349005668, REVEL 0.53, CADD 23.60
- V60I (p.Val60Ile), rs1161714920, gnomAD rs1161714920, NCI-TCGA Cosmic COSV9996, cosmic curated COSV99960, REVEL 0.42, CADD 23.00, Variant assessed as somatic; moderate impact.
- V60G (p.Val60Gly), gnomAD 2-168901510-T-G, REVEL 0.87, CADD 25.70
- V60E (p.Val60Glu), gnomAD 2-168901510-T-A, REVEL 0.87, CADD 26.10
- V60V (p.Val60Val), rs747024214, gnomAD 2-168901511-A-G, CADD 7.95
- A61V (p.Ala61Val), TOPMed rs903875419, gnomAD rs903875419, REVEL 0.70, CADD 26.40
- A61T (p.Ala61Thr), gnomAD 2-168901512-G-A, REVEL 0.64, CADD 24.80
- A61E (p.Ala61Glu), gnomAD 2-168901513-C-A, REVEL 0.81, CADD 24.80
- A61A (p.Ala61Ala), rs368329614, gnomAD 2-168901514-A-T, CADD 6.87
- V62D (p.Val62Asp), gnomAD rs1324745655, REVEL 0.93, CADD 27.00
Public G6PC2 analysis runs
- G6PC2 analysis run — G6PC2 (770 variants) — completed 2026-08-22