MODY: genes and variants
Explore variant evidence for MODY across 7 analyzed proteins (GCK, HNF4A, KCNJ11, HNF1B, PDX1 and 2 more). Linked ClinVar records include 94 pathogenic or likely pathogenic variants, 307 variants of uncertain significance and 153 with conflicting classifications.
Coverage includes proteins already analyzed in CATVariant, not every gene involved in this condition. Database links are associations, not an assessment of clinical gene–disease validity. Computable evidence prioritizes variants for expert review and does not reclassify them. Source labels are pooled across this disease family.
Data updated 2026-10-10. Automated aggregation, not a clinical review date.
Download variant evidence (CSV)
Genes linked to MODY
GCK: Hexokinase-4
It sets the glucose threshold for insulin secretion in pancreatic beta cells and controls hepatic glucose phosphorylation after meals. Heterozygous loss-of-function variants cause GCK-MODY, stronger loss can cause neonatal diabetes, and activating variants can cause hyperinsulinemic hypoglycemia.
68 ClinVar pathogenic / likely pathogenic and 107 uncertain variants in GCK have source records linked to MODY. Association strength is not clinical gene validity.
HNF4A: Hepatocyte nuclear factor 4-alpha
It coordinates transcription of genes involved in hepatic metabolism and pancreatic beta-cell function. Heterozygous pathogenic variants can cause maturity-onset diabetes of the young, often with fetal overgrowth and transient neonatal hyperinsulinemic hypoglycemia in affected families.
9 ClinVar pathogenic / likely pathogenic and 60 uncertain variants in HNF4A have source records linked to MODY. Association strength is not clinical gene validity.
KCNJ11: ATP-sensitive inward rectifier potassium channel 11
Together with SUR1, its ATP-sensitive potassium conductance couples pancreatic beta-cell metabolism to membrane depolarization and insulin secretion. Activating variants cause neonatal diabetes, whereas loss-of-function variants can cause congenital hyperinsulinism.
4 ClinVar pathogenic / likely pathogenic and 80 uncertain variants in KCNJ11 have source records linked to MODY. Association strength is not clinical gene validity.
HNF1B: Hepatocyte nuclear factor 1-beta
It controls developmental and metabolic gene programs in kidney, pancreas, liver, and genital tract. Haploinsufficiency or intragenic pathogenic variants cause a multisystem disorder often featuring renal cysts or malformations, maturity-onset diabetes of the young, hypomagnesemia, and genital abnormalities.
4 ClinVar pathogenic / likely pathogenic and 44 uncertain variants in HNF1B have source records linked to MODY. Association strength is not clinical gene validity.
PDX1: Pancreas/duodenum homeobox protein 1
It directs pancreatic development and later maintains beta-cell identity and insulin transcription. Biallelic severe loss can cause pancreatic agenesis and neonatal diabetes, while heterozygous variants can cause maturity-onset diabetes of the young.
4 ClinVar pathogenic / likely pathogenic and 50 uncertain variants in PDX1 have source records linked to MODY. Association strength is not clinical gene validity.
INS: Insulin
After processing to insulin, it lowers blood glucose by promoting cellular glucose uptake, glycogen and lipid synthesis, and suppression of hepatic glucose production. Pathogenic variants can cause neonatal diabetes, maturity-onset diabetes of the young, or hyperproinsulinemia depending on their effect on folding and secretion.
3 ClinVar pathogenic / likely pathogenic and 13 uncertain variants in INS have source records linked to MODY. Association strength is not clinical gene validity.
ABCC8: ATP-binding cassette sub-family C member 8
It senses cellular nucleotide levels as the regulatory component of pancreatic beta-cell ATP-sensitive potassium channels and thereby couples glucose metabolism to insulin secretion. Loss-of-function variants cause congenital hyperinsulinism, whereas activating variants can cause neonatal diabetes.
2 ClinVar pathogenic / likely pathogenic and 106 uncertain variants in ABCC8 have source records linked to MODY. Association strength is not clinical gene validity.
Where MODY variants cluster
- HNF4A Nuclear receptor (positions 57–132): 3 of 9 ClinVar pathogenic / likely pathogenic variants, 2.1× more than its size predicts.
ClinVar pathogenic and likely pathogenic variants linked to MODY
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| GCK R397H | 397 | Hexokinase | Pathogenic / likely pathogenic (★★★) |
| GCK A378D | 378 | Hexokinase | Pathogenic / likely pathogenic (★★★) |
| GCK T206M | 206 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK E256K | 256 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK R303Q | 303 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK R303W | 303 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK L164P | 164 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK T206P | 206 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK M251V | 251 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK E256Q | 256 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK R447G | 447 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK R447Q | 447 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| ABCC8 R1379H | 1379 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| GCK G44D | 44 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK P59S | 59 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK G72R | 72 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK C129Y | 129 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK G223S | 223 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK M251I | 251 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK I293R | 293 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK L315H | 315 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK G410V | 410 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK R447P | 447 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK G81D | 81 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK W257R | 257 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| HNF1B R304G | 304 | Homeobox | Pathogenic / likely pathogenic (★★) |
| KCNJ11 E282K | 282 | Cytoplasmic | Pathogenic / likely pathogenic (★★) |
| ABCC8 T1515M | 1515 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| GCK G80D | 80 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK S131P | 131 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK E300G | 300 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK L324P | 324 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| HNF1B R295C | 295 | Homeobox | Pathogenic / likely pathogenic (★★) |
| GCK E70K | 70 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK R85W | 85 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK A176G | 176 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK A188V | 188 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK F260S | 260 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK E265K | 265 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK F316Y | 316 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK N391K | 391 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK M393T | 393 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK S453W | 453 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK H50Y | 50 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK I159V | 159 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK V244G | 244 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK Y289C | 289 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK S411F | 411 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| HNF1B M442T | 442 | Pathogenic / likely pathogenic (★★) | |
| HNF4A E278K | 278 | NR LBD | Pathogenic / likely pathogenic (★★) |
| HNF4A E285K | 285 | NR LBD | Pathogenic / likely pathogenic (★★) |
| GCK M251T | 251 | Hexokinase | Pathogenic / likely pathogenic (★) |
| GCK D205G | 205 | Hexokinase | Pathogenic / likely pathogenic (★) |
| GCK D205V | 205 | Hexokinase | Pathogenic / likely pathogenic (★) |
| GCK L164F | 164 | Hexokinase | Pathogenic / likely pathogenic (★) |
| GCK T332M | 332 | Hexokinase | Pathogenic / likely pathogenic (★) |
| HNF4A P297S | 297 | NR LBD | Pathogenic / likely pathogenic (★) |
| KCNJ11 R192C | 192 | Cytoplasmic | Pathogenic / likely pathogenic (★) |
| GCK W167C | 167 | Hexokinase | Pathogenic / likely pathogenic (★) |
| GCK G170V | 170 | Hexokinase | Pathogenic / likely pathogenic (★) |
Showing 60 of 94.
Uncertain variants prioritized for review in MODY
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| GCK M41V | 41 | Hexokinase | Conflicting reports (★) | +7: 2 other pathogenic changes within 3 positions; M41R at the same position is pathogenic; seen in 6.8e-07 of gnomAD DNA copies; REVEL 0.960 |
| GCK I293T | 293 | Hexokinase | Conflicting reports (★) | +7: 3 other pathogenic changes within 3 positions; I293R at the same position is pathogenic; seen in 6.9e-07 of gnomAD DNA copies; REVEL 0.921 |
| GCK F330V | 330 | Hexokinase | Uncertain (★) | +7: 2 other pathogenic changes within 3 positions; F330S at the same position is pathogenic; seen in 6.6e-06 of gnomAD DNA copies; REVEL 0.955 |
| GCK E70Q | 70 | Hexokinase | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; E70K at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.93 |
| GCK L185R | 185 | Hexokinase | Conflicting reports (★) | +6: 3 other pathogenic changes within 3 positions; L185P at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.99 |
| GCK L306P | 306 | Hexokinase | Conflicting reports (★) | +6: 3 other pathogenic changes within 3 positions; L306Q at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.99 |
| GCK D205E | 205 | Hexokinase | Conflicting reports (★) | +6: 5 other pathogenic changes within 3 positions; D205G at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 1.00 |
| GCK E256D | 256 | Hexokinase | Conflicting reports (★) | +6: 3 other pathogenic changes within 3 positions; E256Q at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.99 |
| KCNJ11 R192H | 192 | Cytoplasmic | Conflicting reports (★) | +6: in a 3D region that tolerates change poorly (1R); R192C at the same position is pathogenic; REVEL 0.944 |
| GCK L315F | 315 | Hexokinase | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; L315H at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.88 |
| GCK F316V | 316 | Hexokinase | Conflicting reports (★) | +6: 2 other pathogenic changes within 3 positions; F316Y at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.99 |
| GCK L306R | 306 | Hexokinase | Uncertain (★★) | +6: 3 other pathogenic changes within 3 positions; L306Q at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.99 |
| GCK R85S | 85 | Hexokinase | Uncertain (★) | +6: 2 other pathogenic changes within 3 positions; R85W at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.99 |
Which prediction tools work for MODY
Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.
- MetaLR: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- REVEL: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 91 out of 100
- CATVariant: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- SIFT: 84 out of 100
- AlphaMissense: 76 out of 100
- MutPred2: 67 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- phyloP: 66 out of 100
Same protein, different disease
- Monogenic diabetes also has ClinVar records linked to GCK variants; they fall partly in the same places as the MODY variants (235 pathogenic / likely pathogenic).
- Hyperinsulinemic hypoglycemia, familial, 1 also has ClinVar records linked to GCK variants; they fall in the same places as the MODY variants (7 pathogenic / likely pathogenic).
- Monogenic diabetes also has ClinVar records linked to HNF4A variants; they fall mostly in different places as the MODY variants (50 pathogenic / likely pathogenic).
- Renal cysts and diabetes syndrome also has ClinVar records linked to HNF1B variants; they fall mostly in different places as the MODY variants (71 pathogenic / likely pathogenic).
- Nonpapillary renal cell carcinoma also has ClinVar records linked to HNF1B variants; they fall mostly in different places as the MODY variants (4 pathogenic / likely pathogenic).
- Type 2 diabetes mellitus also has ClinVar records linked to HNF1B variants; they fall mostly in different places as the MODY variants (4 pathogenic / likely pathogenic).
- Diabetes also has ClinVar records linked to KCNJ11 variants; they fall mostly in different places as the MODY variants (12 pathogenic / likely pathogenic).
- Diabetes mellitus, permanent neonatal 3 also has ClinVar records linked to KCNJ11 variants; they fall mostly in different places as the MODY variants (7 pathogenic / likely pathogenic).
- Hyperinsulinemic hypoglycemia, familial, 1 also has ClinVar records linked to KCNJ11 variants; they fall mostly in different places as the MODY variants (7 pathogenic / likely pathogenic).
- Familial hyperinsulinism also has ClinVar records linked to KCNJ11 variants; they fall mostly in different places as the MODY variants (6 pathogenic / likely pathogenic).
- Permanent neonatal diabetes mellitus also has ClinVar records linked to KCNJ11 variants; they fall mostly in different places as the MODY variants (6 pathogenic / likely pathogenic).
- Diabetes also has ClinVar records linked to INS variants; they fall mostly in different places as the MODY variants (12 pathogenic / likely pathogenic).
- Diabetes mellitus, permanent neonatal 3 also has ClinVar records linked to INS variants; they fall mostly in different places as the MODY variants (11 pathogenic / likely pathogenic).
- Type 1 diabetes mellitus also has ClinVar records linked to INS variants; they fall mostly in different places as the MODY variants (8 pathogenic / likely pathogenic).
- Hyperproinsulinemia also has ClinVar records linked to INS variants; they fall mostly in different places as the MODY variants (6 pathogenic / likely pathogenic).
Diseases related to MODY
- Monogenic diabetes, also linked to ABCC8, GCK, HNF1B, HNF4A and 3 more
- Type 2 diabetes mellitus, also linked to ABCC8, GCK, HNF1B, HNF4A and 3 more
- Diabetes, also linked to ABCC8, HNF1B, HNF4A, INS and 2 more
- Permanent neonatal diabetes mellitus, also linked to ABCC8, GCK, INS and KCNJ11
- Hyperinsulinemic hypoglycemia, familial, 1, also linked to ABCC8, GCK and KCNJ11
- Diabetes mellitus, permanent neonatal 3, also linked to ABCC8, INS and KCNJ11
- Familial hyperinsulinism, also linked to ABCC8, GCK and KCNJ11
- Renal cysts and diabetes syndrome, also linked to HNF1B and HNF4A
- Diabetes mellitus, transient neonatal, 2, also linked to ABCC8 and KCNJ11
- Atrial septal defect, also linked to ABCC8
- Pulmonary arterial hypertension, also linked to ABCC8
- Hereditary hyperinsulinism, also linked to ABCC8
Frequently asked questions
Which genes have records linked to MODY?
This view contains 7 analyzed proteins: GCK, HNF4A, KCNJ11, HNF1B, PDX1 and 2 more. Links come from clinical records and association databases. They do not imply that every listed gene is a validated cause, and missing genes may not yet be analyzed.
What do the clinical classifications mean?
Linked records include 94 pathogenic or likely pathogenic variants, 307 variants of uncertain significance and 153 with conflicting classifications. Labels summarize source records; multi-condition records may not make a separate assertion for this disease. Check the original record and review status.
Does the evidence score change a VUS classification?
No. 13 VUS or conflicting variants reach the likely-pathogenic points range on the computable criteria available here. This is a research prioritization signal, not a clinical classification. Patient, family and other required evidence may be missing.
Can I download the variant evidence?
Download the CSV for all 614 variants in the selected disease scope, including clinical labels, review status, evidence criteria, predictor scores, functional measurements and population frequency where available.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from eligible public CATVariant analyses of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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