Blood Sugar & Diabetes

Intronic variant in WFS1 (wolframin) on chromosome 4q22, one of the earliest and most replicated common genetic risk factors for type 2 diabetes, acting through ER stress dysregulation in pancreatic beta cells; the protective A allele tags a haplotype associated with preserved beta-cell insulin secretion

Intergenic variant between GRB14 and COBLL1 that acts as an eQTL for GRB14 in adipose tissue, shifting body fat toward peripheral (hip and limb) versus central (visceral) deposition

Intronic variant in YKT6 immediately downstream of GCK; the A allele is a GWAS-identified common risk allele for type 2 diabetes with a modest additive effect on fasting glucose dysregulation

Intronic GIPR variant that reduces functional GIP receptor expression via altered splicing, impairing the incretin-mediated insulin response while paradoxically lowering BMI

ENPP1 K121Q variant that increases ENPP1 binding affinity to the insulin receptor by 2–3 fold, blunting insulin signaling and raising insulin resistance risk.

Pathogenic glucokinase nonsense variant introducing a premature stop codon that abolishes protein function, causing autosomal dominant maturity-onset diabetes of the young type 2 (MODY2) in heterozygous carriers — the original nonsense mutation in GCK identified in 1992

Pathogenic glucokinase missense variant that nearly abolishes enzyme activity (Kcat/S0.5 ratio 0.0001 vs wild-type), causing autosomal dominant maturity-onset diabetes of the young type 2 (MODY2) in heterozygous carriers — lifelong mild stable fasting hyperglycemia that does not require pharmacological treatment

Pathogenic glucokinase missense variant that nearly abolishes enzyme activity, causing autosomal dominant maturity-onset diabetes of the young type 2 (MODY2) in heterozygous carriers and permanent neonatal diabetes when homozygous

Pathogenic glucokinase missense variant that raises the beta-cell glucose sensing threshold, causing lifelong mild fasting hyperglycemia characteristic of MODY2 — a condition that rarely needs treatment but is frequently misdiagnosed as type 1 or type 2 diabetes

Pathogenic glucokinase missense variant causing MODY2 — mild, stable fasting hyperglycemia that typically requires no pharmacologic treatment

Regulatory variant upstream of CDKN2A/CDKN2B at the 9p21 locus; the T risk allele (major, ~83% globally) impairs cyclin-dependent kinase inhibitor expression and reduces beta-cell proliferative capacity, increasing type 2 diabetes risk by ~24% per allele

Intergenic variant near ADRA2A that modulates alpha-2A adrenergic receptor expression in pancreatic beta cells, influencing cAMP levels, insulin granule docking, and fasting glucose

Intronic TCF7L2 variant tagging the diabetes-risk haplotype and associated with elevated proinsulin/insulin ratio through impaired beta-cell insulin processing

Intergenic variant near ENPP1-associated regulatory loci; T allele is associated with altered ENPP1 expression and modest modulation of insulin receptor signaling tone through regulatory network effects.

Primary tag SNP at the HHEX/IDE locus on chromosome 10q23, one of the earliest and most replicated T2D GWAS hits, linked to reduced HHEX expression, impaired beta-cell development, and blunted first-phase insulin secretion

Synonymous PTPRS variant associated with increased type 2 diabetes risk in men with the homozygous risk genotype, acting through impaired pancreatic beta-cell insulin secretion

3-prime UTR variant in the SLC30A8 zinc transporter gene that alters ZnT8 mRNA expression via allele-specific mechanisms, providing additional signal on zinc-mediated insulin processing and type 2 diabetes susceptibility at this locus

Common coding variant in the HNF1A transcription factor dimerization domain that modestly reduces beta-cell function and transactivation activity, raising LDL cholesterol and lowering CRP, while increasing type 2 diabetes risk in normal-weight individuals and accelerating diabetes onset in MODY3 carriers

Upstream regulatory variant in IGF2BP2 that shifts mRNA isoform balance in adipose tissue and pancreatic islets, impairing insulin secretion and increasing insulin resistance risk, with moderate evidence for type 2 diabetes susceptibility

Intronic regulatory variant that reduces ADCY5 expression in pancreatic islets, impairing glucose-stimulated cAMP production and insulin secretion, and raising fasting glucose and type 2 diabetes risk

Intronic TCF7L2 depth variant replicated across multiple populations as a secondary type 2 diabetes risk signal, likely tagging a distinct regulatory element that modulates Wnt/TCF7L2-driven proglucagon expression and incretin signaling depth

Second TCF7L2 diabetes variant - compounds risk with rs7903146

Intronic INSR variant that may alter insulin receptor expression or isoform balance, linked to insulin signaling and psychiatric risk

Zinc transporter 8 variant affecting zinc loading into insulin granules, influencing insulin crystallization, secretion, and type 2 diabetes risk

Intronic variant in THADA, a gene encoding a calcium channel-regulating protein; the C allele increases PCOS risk in Asian women and influences pancreatic beta-cell function in the context of type 2 diabetes

Pathogenic nonsense variant in HNF4A causing MODY1 — a progressive, autosomal dominant monogenic diabetes with neonatal hypoglycemia and sulfonylurea sensitivity

Upstream regulatory variant in G6PC2 that modulates pancreatic beta-cell glucose-sensing; the T allele reduces G6PC2 expression and lowers fasting blood glucose

Intronic variant in TSPAN8 (Tetraspanin 8) associated with reduced insulin secretion and type 2 diabetes risk; the G allele impairs pancreatic beta-cell and alpha-cell function, reducing insulinogenic response to glucose

Regulatory intronic variant within ANRIL (CDKN2B-AS1) at the 9p21.3 locus; the T risk allele is associated with substantially elevated risk of myocardial infarction, brain aneurysm, and type 2 diabetes through ANRIL-mediated dysregulation of cellular senescence and beta-cell proliferation

Regulatory 3'UTR variant in the melatonin receptor 1B gene that affects MTNR1B expression levels and plasma melatonin dynamics, modulating the circadian suppression of pancreatic insulin secretion and metabolic health

Intronic GLIS3 variant in which the rare A allele modestly elevates TSH, reflecting reduced thyroid transcriptional activity; the same gene drives pancreatic beta cell development, linking thyroid-axis regulation to metabolic energy balance

A guanine duplication in the 3'-UTR of PTPN1 (PTP1B) that increases mRNA stability and skeletal muscle PTP1B expression, amplifying negative regulation of the insulin receptor and contributing to insulin resistance.

Intronic tag SNP at the 12q24 locus that captures SH2B3/LNK regulatory variation, increasing risk for type 1 diabetes, juvenile idiopathic arthritis, and other autoimmune diseases; also associated with modest effects on lipid levels and serum urate

Synonymous variant in the tyrosine kinase domain of the insulin receptor; the A risk allele (plus-strand) is associated with PCOS susceptibility and insulin resistance in lean women, possibly through altered mRNA processing near the ATP-binding site of the receptor kinase domain

Missense variant in the skeletal muscle glycogen-targeting subunit of protein phosphatase 1 (PP1); reduces effective PP1 activity at the glycogen particle, impairing insulin-stimulated glycogen synthesis and increasing type 2 diabetes risk

Missense variant in HNF4A causing hepatocyte-specific loss of transcriptional activity; associated with early-onset type 2 diabetes and metabolic syndrome, particularly in Latino and Asian populations

Missense variant in insulin receptor substrate 1 that impairs tyrosine phosphorylation and PI3-kinase recruitment, reducing insulin signaling and increasing type 2 diabetes risk and oral antidiabetes drug failure

Intronic variant tagging the HNF4A P2 promoter risk haplotype; the G allele strongly elevates type 2 diabetes risk in Ashkenazi Jewish populations (OR ~1.70) and modestly in Scandinavians (OR ~1.14) by reducing beta-cell-specific HNF4A isoform expression

Rare HNF1B splice-region intronic variant of uncertain significance, found near exon 9 of the HNF1B gene and submitted to ClinVar in the context of renal cysts and diabetes syndrome (MODY5 / HNF1B-related disease)

Pathogenic missense variant in glucokinase that raises the glucose set-point for insulin secretion, causing mild stable fasting hyperglycemia (heterozygous MODY2) or severe permanent neonatal diabetes (homozygous)

Intronic INSR variant associated with PCOS susceptibility and metabolic syndrome risk through altered insulin receptor signaling

Synonymous exon 13 variant in the insulin receptor gene; the A allele has been associated with schizoaffective disorder and modestly with body height in psychiatric cohort studies

Missense variant that impairs PAX4's ability to repress insulin and glucagon promoters, reducing beta-cell mass and insulin secretion capacity; strongly associated with type 2 diabetes and younger age of onset in East and Southeast Asian populations

Intronic variant in KCNQ1's imprinted region, tagging the same LD block as established East Asian T2D susceptibility variants that impair insulin secretion through altered Kv7.1 potassium channel function in pancreatic beta cells

Intronic GCK variant 38 bp downstream of exon 7; the A allele (GRCh38 reference, minor at ~43% globally) has been associated with gestational diabetes risk in some small studies, though evidence is limited and inconsistent across populations

TRIB3 pseudokinase missense variant that increases Akt inhibition, impairing insulin signaling across liver, muscle, and pancreatic beta cells, with associated risk for insulin resistance and type 2 diabetes

3'UTR variant in the zinc transporter ZnT8 gene that disrupts miRNA binding sites, altering ZnT8 expression in pancreatic beta cells and influencing type 2 diabetes, type 1 diabetes, and gestational diabetes risk

Regulatory tagging SNP near SGK1 (serum/glucocorticoid regulated kinase 1) — the major T allele is associated with salt-sensitive blood pressure, higher systolic BP on high-sodium diets, and attenuated plasma renin activity suppression on low-sodium diets; the minor C allele provides partial protection from salt-driven blood pressure excursions.

Intronic TCF7L2 variant tagging a distinct haplotype with emerging evidence for effects on beta cell transcriptional regulation through the Wnt/beta-catenin axis

Regulates insulin signaling efficiency and cellular glucose uptake

Intronic PTPN1 variant in the 100-kb haplotype block; T allele associated with more favorable cholesterol profile (lower total and LDL cholesterol) in lean individuals

Rare gain-of-function variant causing autosomal dominant metabolic syndrome (AOMS3) — early-onset central obesity, insulin resistance, hypertriglyceridemia, and type 2 diabetes

Intronic PTPN1 tag SNP within the 100-kb PTP1B insulin-resistance haplotype block; the minor C allele co-segregates with the risk haplotype associated with elevated PTP1B expression, impaired insulin signaling, and lipid dysregulation

Intronic PTPN1 tag SNP within the 100-kb insulin-resistance haplotype block; carriers of the T allele show reduced weight loss response to lifestyle intervention and blunted leptin reduction, consistent with elevated PTP1B activity dampening insulin and leptin signaling

Intronic variant in serine racemase that alters D-serine production in pancreatic beta cells, modulating NMDA receptor signaling and glucose-stimulated insulin secretion; C allele associated with increased type 2 diabetes and gestational diabetes risk, particularly in East Asian populations

Pathogenic glucokinase missense variant causing maturity-onset diabetes of the young type 2 (MODY2) — lifelong mild fasting hyperglycemia that rarely requires treatment and is frequently misdiagnosed as type 1 or type 2 diabetes

Common intronic variant near glucokinase that raises fasting glucose by impairing the pancreatic glucose-sensing threshold; each A allele adds ~0.062 mmol/L to fasting glucose and modestly reduces beta-cell function

Intronic PTPRS variant that tags elevated type 2 diabetes risk in both sexes through increased receptor protein tyrosine phosphatase sigma activity, which dephosphorylates insulin-signalling substrates and attenuates both pancreatic insulin secretion and peripheral insulin sensitivity

Common intronic variant in HNF4A associated with modestly elevated type 2 diabetes risk via reduced pancreatic beta-cell function; identified through GWAS in South Asian and European populations

Coding variant in the islet glucose-6-phosphatase that fine-tunes the fasting glucose setpoint by altering G6PC2 protein abundance in pancreatic beta cells

Regulatory variant near HHEX and IDE linked to impaired beta-cell development and insulin secretion, one of the earliest and most-replicated T2D GWAS loci

Severe Class II G6PD deficiency variant (c.563C>T, p.Ser188Phe) causing less than 10% residual enzyme activity and high risk of acute hemolytic anemia from drugs, fava beans, and infections; prevalent across Mediterranean, Middle Eastern, and South Asian populations

A regulatory 3' UTR variant in KCNJ11 that modulates KATP channel expression via microRNA binding, influencing insulin secretion and sulfonylurea drug response

Controls the pancreatic beta-cell potassium channel that regulates insulin secretion and determines sulfonylurea drug response

Secondary T2D risk variant at the 9p21 CDKN2A/B locus within ANRIL (CDKN2B-AS1); the T risk allele impairs glucose-stimulated pancreatic beta-cell proliferation, conferring a modest but independently replicated ~8% increased type 2 diabetes risk per allele

Multi-allelic pathogenic locus — both H90P (T>G) and H90R (T>C) disrupt the DYRK1B DH box, causing AOMS3 (early-onset central obesity, type 2 diabetes, hypertension, coronary artery disease) via impaired kinase maturation

Intronic HNF4A tag SNP associated with altered bile acid synthesis regulation through modified HNF4A-driven CYP7A1 expression; linked to primary biliary cholangitis progression in a single Japanese cohort study

Intronic PTPN1 tag SNP in the PTP1B regulatory LD block; the minor A allele is associated with elevated total and LDL cholesterol in lean men and tags haplotypes linked to altered insulin signaling and metabolic risk

Intronic variant 80 bp from rs6031552 within the HNF4A P2 promoter haplotype block; part of a nine-SNP panel associated with insulin resistance and lower HDL in carriers

Intronic variant tagging the HNF4A P2 promoter haplotype; carriers have modestly elevated risk for impaired insulin secretion and type 2 diabetes

Intronic PTPN1 tag SNP within the 100-kb T2D-risk haplotype block — carriers of the G allele have modestly higher PTP1B activity, reducing insulin and leptin signal duration and raising LDL cholesterol risk in lean individuals

Pleiotropic 12q24 locus variant in SH2B3 (LNK) modulating JAK-STAT cytokine signaling, with associations spanning blood pressure, type 2 diabetes, celiac disease, and coronary artery disease

Intronic SLC2A9 variant tagging a regulatory signal for renal urate reabsorption; the C allele is associated with higher serum uric acid and elevated gout risk, with substantially stronger effects in women; the T allele confers modestly reduced urate and partial gout protection

Intronic variant in the major renal urate transporter; the G allele tags a haplotype associated with reduced urate excretion and elevated serum uric acid, while the C allele is protective; this is an independent signal at the SLC2A9 locus distinct from the Arg265His missense variant (rs3733591)

Tag SNP for the insulin gene VNTR promoter — shorter Class I repeats raise T1D risk by reducing thymic insulin expression

Intergenic variant near CTRB1/CTRB2 that regulates chymotrypsinogen expression and GLP-1-stimulated insulin secretion; T allele carriers have mildly impaired incretin-driven beta-cell response and modestly elevated type 2 diabetes risk

Missense variant in glucose-6-phosphate dehydrogenase causing Class III G6PD deficiency (~50% residual enzyme activity), associated with hemolytic anemia triggered by fava beans, infections, and specific drugs

Intronic GCKR enhancer variant on the CGG regulatory haplotype; the G allele increases FOXA2-driven GCKR expression in the liver, boosting GKRP protein levels and glucokinase inhibition, resulting in elevated fasting glucose and the characteristic GCKR metabolic trade-off

Intronic GCKR enhancer variant that modulates FOXA2-driven GCKR expression in liver; the C allele reduces GCKR expression and weakens hepatic glucokinase braking, contributing to the glucose-triglyceride trade-off pattern characteristic of the GCKR locus — lower fasting glucose and insulin at the cost of elevated triglycerides and NAFLD susceptibility

Main type 2 diabetes risk variant - strongly modulated by dietary fat

Downstream regulatory variant 10 kb 3' of PTPN1 (PTP1B) associated with type 2 diabetes risk (OR 1.43) and moderate obesity in a French population study; tags the regulatory region flanking the PTP1B negative-regulator locus

Regulatory variant in SGK1 (serum/glucocorticoid regulated kinase 1) — the minor G allele is associated with improved insulin secretion in lean individuals and a modest reduction in type 2 diabetes prevalence, while also modifying blood pressure response to high dietary salt intake.

Intronic PTPN1 variant tagging a haplotype block associated with reduced insulin sensitivity, higher fasting insulin, and elevated lipids through altered PTP1B expression