Hyperinsulinemic hypoglycemia, familial, 1: genes and variants
Explore variant evidence for Hyperinsulinemic hypoglycemia, familial, 1 across 3 analyzed proteins (ABCC8, KCNJ11, GCK). Linked ClinVar records include 45 pathogenic or likely pathogenic variants, 163 variants of uncertain significance and 43 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 Hyperinsulinemic hypoglycemia, familial, 1
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.
31 ClinVar pathogenic / likely pathogenic and 161 uncertain variants in ABCC8 have source records linked to Hyperinsulinemic hypoglycemia, familial, 1. 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.
7 ClinVar pathogenic / likely pathogenic and 35 uncertain variants in KCNJ11 have source records linked to Hyperinsulinemic hypoglycemia, familial, 1. Association strength is not clinical gene validity.
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.
7 ClinVar pathogenic / likely pathogenic and 10 uncertain variants in GCK have source records linked to Hyperinsulinemic hypoglycemia, familial, 1. Association strength is not clinical gene validity.
Where Hyperinsulinemic hypoglycemia, familial, 1 variants cluster
- ABCC8 ABC transporter 2 (positions 1344–1578): 15 of 31 ClinVar pathogenic / likely pathogenic variants, 3.3× more than its size predicts.
- ABCC8 Cytoplasmic (positions 1175–1248): 4 of 31 ClinVar pathogenic / likely pathogenic variants, 2.8× more than its size predicts.
ClinVar pathogenic and likely pathogenic variants linked to Hyperinsulinemic hypoglycemia, familial, 1
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| ABCC8 R1182W | 1182 | ABC transmembrane type-1 2 | Pathogenic / likely pathogenic (★★) |
| ABCC8 R1182Q | 1182 | ABC transmembrane type-1 2 | Pathogenic / likely pathogenic (★★) |
| KCNJ11 R34H | 34 | Cytoplasmic | Pathogenic / likely pathogenic (★★) |
| ABCC8 G7R | 7 | Extracellular | Pathogenic / likely pathogenic (★★) |
| ABCC8 Q444H | 444 | ABC transmembrane type-1 1 | Pathogenic / likely pathogenic (★★) |
| ABCC8 G1383R | 1383 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| ABCC8 S1386F | 1386 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| ABCC8 R1393C | 1393 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| ABCC8 P1413L | 1413 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| ABCC8 A1457T | 1457 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| ABCC8 L1459R | 1459 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| ABCC8 R1493Q | 1493 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| ABCC8 E1506K | 1506 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| GCK G44S | 44 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK E256K | 256 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| KCNJ11 R136C | 136 | Extracellular | Pathogenic / likely pathogenic (★★) |
| KCNJ11 R206H | 206 | Cytoplasmic | Pathogenic / likely pathogenic (★★) |
| KCNJ11 P254L | 254 | Cytoplasmic | Pathogenic / likely pathogenic (★★) |
| ABCC8 R168C | 168 | Extracellular | Pathogenic / likely pathogenic (★★) |
| ABCC8 S1385P | 1385 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| ABCC8 G1400R | 1400 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| ABCC8 E128K | 128 | Cytoplasmic | Pathogenic / likely pathogenic (★★) |
| ABCC8 R841G | 841 | ABC transporter 1 | Pathogenic / likely pathogenic (★★) |
| GCK S453L | 453 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| ABCC8 D1471N | 1471 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| ABCC8 L1543P | 1543 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| GCK E265K | 265 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| GCK R447Q | 447 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| ABCC8 N188S | 188 | Cytoplasmic | Pathogenic / likely pathogenic (★★) |
| ABCC8 L1565P | 1565 | ABC transporter 2 | Pathogenic / likely pathogenic (★★) |
| KCNJ11 W91R | 91 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| ABCC8 G111R | 111 | Transmembrane | Pathogenic / likely pathogenic (★★) |
| GCK K90T | 90 | Hexokinase | Pathogenic / likely pathogenic (★★) |
| ABCC8 A1184E | 1184 | ABC transmembrane type-1 2 | Pathogenic / likely pathogenic (★) |
| ABCC8 A1184V | 1184 | ABC transmembrane type-1 2 | Pathogenic / likely pathogenic (★) |
| ABCC8 R836Q | 836 | ABC transporter 1 | Pathogenic / likely pathogenic (★) |
| ABCC8 A1390P | 1390 | ABC transporter 2 | Pathogenic / likely pathogenic (★) |
| KCNJ11 R34G | 34 | Cytoplasmic | Pathogenic / likely pathogenic (★) |
| ABCC8 G1484V | 1484 | ABC transporter 2 | Pathogenic / likely pathogenic (★) |
| GCK V389L | 389 | Hexokinase | Pathogenic / likely pathogenic (★) |
| KCNJ11 G289V | 289 | Cytoplasmic | Pathogenic / likely pathogenic (★) |
| ABCC8 F41S | 41 | Transmembrane | Pathogenic / likely pathogenic (★) |
| ABCC8 C435Y | 435 | ABC transmembrane type-1 1 | Pathogenic / likely pathogenic (★) |
| ABCC8 G684D | 684 | ABC transporter 1 | Pathogenic / likely pathogenic (★) |
| ABCC8 G716V | 716 | ABC transporter 1 | Pathogenic / likely pathogenic |
Which prediction tools work for Hyperinsulinemic hypoglycemia, familial, 1
Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.
- CADD: 96 out of 100
- REVEL: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MetaLR: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- phyloP: 83 out of 100
- SIFT: 83 out of 100
- MutPred2: 71 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- AlphaMissense: 61 out of 100
Same protein, different disease
- Type 2 diabetes mellitus also has ClinVar records linked to ABCC8 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (27 pathogenic / likely pathogenic).
- Hereditary hyperinsulinism also has ClinVar records linked to ABCC8 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (22 pathogenic / likely pathogenic).
- Familial hyperinsulinism also has ClinVar records linked to ABCC8 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (20 pathogenic / likely pathogenic).
- Diabetes mellitus, transient neonatal, 2 also has ClinVar records linked to ABCC8 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (19 pathogenic / likely pathogenic).
- Diabetes mellitus, permanent neonatal 3 also has ClinVar records linked to ABCC8 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (17 pathogenic / likely pathogenic).
- Diabetes also has ClinVar records linked to KCNJ11 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 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 Hyperinsulinemic hypoglycemia, familial, 1 variants (7 pathogenic / likely pathogenic).
- Familial hyperinsulinism also has ClinVar records linked to KCNJ11 variants; they fall partly in the same places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (6 pathogenic / likely pathogenic).
- Permanent neonatal diabetes mellitus also has ClinVar records linked to KCNJ11 variants; they fall partly in the same places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (6 pathogenic / likely pathogenic).
- Type 2 diabetes mellitus also has ClinVar records linked to KCNJ11 variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (6 pathogenic / likely pathogenic).
- Monogenic diabetes also has ClinVar records linked to GCK variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (235 pathogenic / likely pathogenic).
- MODY also has ClinVar records linked to GCK variants; they fall mostly in different places as the Hyperinsulinemic hypoglycemia, familial, 1 variants (68 pathogenic / likely pathogenic).
Diseases related to Hyperinsulinemic hypoglycemia, familial, 1
- Monogenic diabetes, also linked to ABCC8, GCK and KCNJ11
- MODY, also linked to ABCC8, GCK and KCNJ11
- Type 2 diabetes mellitus, also linked to ABCC8, GCK and KCNJ11
- Familial hyperinsulinism, also linked to ABCC8, GCK and KCNJ11
- Permanent neonatal diabetes mellitus, also linked to ABCC8, GCK and KCNJ11
- Diabetes, also linked to ABCC8 and KCNJ11
- Diabetes mellitus, permanent neonatal 3, also linked to ABCC8 and KCNJ11
- 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
- Leucine-induced hypoglycemia, also linked to ABCC8
Frequently asked questions
Which genes have records linked to Hyperinsulinemic hypoglycemia, familial, 1?
This view contains 3 analyzed proteins: ABCC8, KCNJ11, GCK. 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 45 pathogenic or likely pathogenic variants, 163 variants of uncertain significance and 43 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. 0 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 286 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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