INS

insulin, the group of Neuropeptides

Basic information

Region (hg38): 11:2159778-2161221

Previous symbols: [ "IDDM2", "IDDM1" ]

Links

ENSG00000254647 ∙ NCBI:3630 ∙ OMIM:176730 ∙ HGNC:6081 ∙ Uniprot:P01308 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• transient neonatal diabetes mellitus (Strong), mode of inheritance: AD
• permanent neonatal diabetes mellitus (Strong), mode of inheritance: AD
• transient neonatal diabetes mellitus (Strong), mode of inheritance: AR
• maturity-onset diabetes of the young type 10 (Strong), mode of inheritance: AD
• diabetes mellitus, permanent neonatal 4 (Strong), mode of inheritance: AD
• type 1 diabetes mellitus 2 (Strong), mode of inheritance: AD
• hyperproinsulinemia (Strong), mode of inheritance: AD
• diabetes mellitus, permanent neonatal 4 (Strong), mode of inheritance: AR
• maturity-onset diabetes of the young (Supportive), mode of inheritance: AD
• permanent neonatal diabetes mellitus (Supportive), mode of inheritance: AD
• hyperproinsulinemia (Limited), mode of inheritance: AD
• maturity-onset diabetes of the young type 10 (Strong), mode of inheritance: AD
• diabetes mellitus, permanent neonatal 4 (Strong), mode of inheritance: AD
• diabetes mellitus, permanent neonatal 4 (Strong), mode of inheritance: AR
• monogenic diabetes (Definitive), mode of inheritance: AR
• monogenic diabetes (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Diabetes mellitus, permanent neonatal 4	AD	Endocrine	Individuals may manifest in infancy with findings including intrauterine growth retardation, postnatal growth deficiency, and signs of diabetes mellitus (eg, hyperglycemia, glycosuria), as well as severe dehydration, and recognition can allow preventive measures related to potential sequelae, surveillance (eg, with blood glucose monitoring as well as surveillance for other common sequelae of diabetes mellitus affecting systems such as the renal and ophthalmogic systems); In the case of an acute diabetic crisis, rapid treatment (eg, with rehydration and IV insulin, transitioning to SQ insulin when stable) is indicated, though rapid-acting and (non-continuous) short-acting insulin preparations may result in severe hypoglycemia in young patients	Endocrine	815812; 288074; 381941; 6424111; 3512591; 17855560; 18451997; 18162506; 18192540; 18171712; 20301620

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the INS gene.

• not provided (46 variants)
• Maturity-onset diabetes of the young type 10 (29 variants)
• Neonatal insulin-dependent diabetes mellitus (28 variants)
• not specified (27 variants)
• Permanent neonatal diabetes mellitus (22 variants)
• Diabetes mellitus, permanent neonatal 4 (21 variants)
• Transient Neonatal Diabetes, Dominant/Recessive (20 variants)
• Neonatal diabetes mellitus (13 variants)
• Maturity onset diabetes mellitus in young (9 variants)
• INS-related condition (7 variants)
• Autosomal recessive DOPA responsive dystonia (7 variants)
• Inborn genetic diseases (6 variants)
• Hyperproinsulinemia (5 variants)
• Type 1 diabetes mellitus 2 (4 variants)
• Type 2 diabetes mellitus (3 variants)
• Diabetes mellitus type 1 (3 variants)
• Diabetes mellitus (2 variants)
• Hyperproinsulinemia;Type 1 diabetes mellitus 2;Maturity-onset diabetes of the young type 10;Diabetes mellitus, permanent neonatal 4 (1 variants)
• Maturity-onset diabetes of the young type 10;Hyperproinsulinemia;Type 1 diabetes mellitus 2;Diabetes mellitus, permanent neonatal 4 (1 variants)
• Hypoinsulinemia (1 variants)
• Hyperproinsulinemia;Type 1 diabetes mellitus 2;Diabetes mellitus, permanent neonatal 4;Maturity-onset diabetes of the young type 10 (1 variants)
• Type 1 diabetes mellitus 2;Maturity-onset diabetes of the young type 10;Diabetes mellitus, permanent neonatal 4;Hyperproinsulinemia (1 variants)
• Type 1 diabetes mellitus 2;Hyperproinsulinemia;Maturity-onset diabetes of the young type 10 (1 variants)
• Type 1 diabetes mellitus 2;Maturity-onset diabetes of the young type 10;Hyperproinsulinemia;Diabetes mellitus, permanent neonatal 4 (1 variants)
• Diabetes mellitus, permanent neonatal 4;Maturity-onset diabetes of the young type 10;Hyperproinsulinemia;Type 1 diabetes mellitus 2 (1 variants)
• Monogenic diabetes (1 variants)
• Hyperproinsulinemia;Maturity-onset diabetes of the young type 10;Diabetes mellitus, permanent neonatal 4;Type 1 diabetes mellitus 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the INS gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	6		7
missense	1	14	18			33
nonsense		1				1
start loss		1	1			2
frameshift		1				1
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region			1			1
non coding			10	11	6	27
Total	1	17	31	17	6

Highest pathogenic variant AF is 0.00000657

Variants in INS

This is a list of pathogenic ClinVar variants found in the INS region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
11-2159793-T-C		Permanent neonatal diabetes mellitus	not provided (-)
11-2159803-C-T		INS-related disorder	Likely benign (Aug 05, 2021)
11-2159810-G-A		Maturity-onset diabetes of the young type 10 • Transient Neonatal Diabetes, Dominant/Recessive • Neonatal insulin-dependent diabetes mellitus	Conflicting classifications of pathogenicity (Jan 13, 2018)
11-2159824-C-T		Maturity-onset diabetes of the young type 10 • Transient Neonatal Diabetes, Dominant/Recessive • Neonatal insulin-dependent diabetes mellitus	Conflicting classifications of pathogenicity (Jan 13, 2018)
11-2159830-T-G		Maturity onset diabetes mellitus in young • Autosomal recessive DOPA responsive dystonia • Transient Neonatal Diabetes, Dominant/Recessive • Maturity-onset diabetes of the young type 10 • Type 1 diabetes mellitus 2 • Diabetes mellitus, permanent neonatal 4 • Hyperproinsulinemia • Diabetes mellitus type 1	Conflicting classifications of pathogenicity (Jul 14, 2021)
11-2159843-G-A		not specified • Transient Neonatal Diabetes, Dominant/Recessive • Maturity onset diabetes mellitus in young • Autosomal recessive DOPA responsive dystonia • Maturity-onset diabetes of the young type 10 • Hypoinsulinemia	Benign/Likely benign (Aug 02, 2017)
11-2159850-G-A		Transient Neonatal Diabetes, Dominant/Recessive • Maturity-onset diabetes of the young type 10 • Neonatal insulin-dependent diabetes mellitus	Conflicting classifications of pathogenicity (Jan 12, 2018)
11-2159859-C-A		Neonatal diabetes mellitus	Likely pathogenic (-)
11-2159859-CAGT-C		not specified • Neonatal insulin-dependent diabetes mellitus	Conflicting classifications of pathogenicity (Apr 04, 2017)
11-2159862-T-C		Permanent neonatal diabetes mellitus • Diabetes mellitus, permanent neonatal 4	Likely risk allele (-)
11-2159863-A-C		Neonatal diabetes mellitus	Likely pathogenic (-)
11-2159866-TCTC-T			Uncertain significance (Nov 07, 2023)
11-2159868-T-A			Uncertain significance (May 07, 2023)
11-2159877-T-C		Permanent neonatal diabetes mellitus • Diabetes mellitus, permanent neonatal 4	Conflicting classifications of pathogenicity (Nov 06, 2021)
11-2159883-G-C		Permanent neonatal diabetes mellitus • Diabetes mellitus, permanent neonatal 4	Likely risk allele (-)
11-2159886-C-T			Uncertain significance (May 23, 2023)
11-2159892-C-A		Neonatal diabetes mellitus	Likely pathogenic (-)
11-2159893-T-A		not specified • Neonatal insulin-dependent diabetes mellitus	Uncertain significance/Uncertain risk allele (Mar 22, 2016)
11-2159895-G-C		Maturity-onset diabetes of the young type 10 • Neonatal insulin-dependent diabetes mellitus	Conflicting classifications of pathogenicity (Sep 07, 2017)
11-2159896-T-G			Likely pathogenic (Jan 30, 2018)
11-2159898-C-G		Permanent neonatal diabetes mellitus	not provided (-)
11-2159898-C-T		Diabetes mellitus, permanent neonatal 4 • Neonatal diabetes mellitus • Permanent neonatal diabetes mellitus	Conflicting classifications of pathogenicity (Jun 18, 2014)
11-2159899-A-G		Diabetes mellitus • Type 1 diabetes mellitus 2	Likely risk allele (-)
11-2159901-C-T		INS-related disorder	Likely pathogenic (Jul 19, 2023)
11-2159906-T-C		INS-related disorder	Likely benign (Oct 20, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
INS	protein_coding	protein_coding	ENST00000397262	2	1563

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.301	0.629	123864	0	1	123865	0.00000404

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.900	44	64.3	0.684	0.00000387	675
Missense in Polyphen		12	27.822	0.43132		284
Synonymous	-0.506	32	28.6	1.12	0.00000150	243
Loss of Function	1.39	1	3.99	0.251	2.70e-7	30

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
• Disease: DISEASE: Hyperproinsulinemia (HPRI) [MIM:616214]: An autosomal dominant condition characterized by elevated levels of serum proinsulin-like material. {ECO:0000269|PubMed:1601997, ECO:0000269|PubMed:2196279, ECO:0000269|PubMed:3470784, ECO:0000269|PubMed:4019786}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, insulin-dependent, 2 (IDDM2) [MIM:125852]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:18192540}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, permanent neonatal (PNDM) [MIM:606176]: A rare form of diabetes distinct from childhood- onset autoimmune diabetes mellitus type 1. It is characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Permanent neonatal diabetes requires lifelong therapy. {ECO:0000269|PubMed:17855560, ECO:0000269|PubMed:18162506}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Maturity-onset diabetes of the young 10 (MODY10) [MIM:613370]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:18162506, ECO:0000269|PubMed:18192540, ECO:0000269|PubMed:20226046, ECO:0000269|PubMed:25423173}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Regulation of lipolysis in adipocytes - Homo sapiens (human);Type I diabetes mellitus - Homo sapiens (human);Type II diabetes mellitus - Homo sapiens (human);Insulin resistance - Homo sapiens (human);Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human);Oocyte meiosis - Homo sapiens (human);HIF-1 signaling pathway - Homo sapiens (human);Longevity regulating pathway - multiple species - Homo sapiens (human);Autophagy - animal - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);Regulation of actin cytoskeleton - Homo sapiens (human);Maturity onset diabetes of the young - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Prostate cancer - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);Aldosterone-regulated sodium reabsorption - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Phospholipase D signaling pathway - Homo sapiens (human);Prolactin signaling pathway - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Ovarian steroidogenesis - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Insulin secretion - Homo sapiens (human);Progesterone-mediated oocyte maturation - Homo sapiens (human);Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics;Leucine Stimulation on Insulin Signaling;Glibenclamide Action Pathway;Gliclazide Action Pathway;Insulin Signalling;Pancreas Function;Repaglinide Action Pathway;Nateglinide Action Pathway;IGF-Core;Selenium Micronutrient Network;Vitamin B12 Metabolism;Folate Metabolism;Cori Cycle;White fat cell differentiation;AGE-RAGE pathway;Adipogenesis;Cardiac Progenitor Differentiation;Differentiation Pathway;Regulation of beta-cell development;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;Leptin Insulin Overlap;White fat cell differentiation;PI3K-Akt Signaling Pathway;Senescence and Autophagy in Cancer;Glucose Homeostasis;Signal Transduction;Peptide hormone metabolism;Vesicle-mediated transport;insulin signaling pathway;Membrane Trafficking;IRS activation;Signal attenuation;Post-translational protein modification;Insulin receptor signalling cascade;Insulin receptor recycling;Signaling by Insulin receptor;Metabolism of proteins;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;ATF-2 transcription factor network;insulin Mam;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;Transport to the Golgi and subsequent modification;Asparagine N-linked glycosylation;growth hormone signaling pathway;Insulin processing;Signaling events mediated by TCPTP;PIP3 activates AKT signaling;FOXA1 transcription factor network;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;Arf6 trafficking events;COPI-mediated anterograde transport;GPCR signaling-G alpha i;Signaling by Receptor Tyrosine Kinases;ER to Golgi Anterograde Transport;Intracellular signaling by second messengers;Insulin Pathway;Insulin-mediated glucose transport;Signaling events mediated by PTP1B;FOXA2 and FOXA3 transcription factor networks;insulin (Consensus)

Intolerance Scores

• loftool: 0.0384
• rvis_EVS: -0.08
• rvis_percentile_EVS: 47.79

Haploinsufficiency Scores

• hipred: N
• hipred_score: 0.158
• ghis: 0.399

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.968

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Low	Low
Primary Immunodeficiency	Medium	Low	Medium
Cancer	Low	Low	Low

Mouse Genome Informatics

• Gene name: Ins2
• Phenotype: immune system phenotype; renal/urinary system phenotype; skeleton phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; vision/eye phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype

Zebrafish Information Network

• Gene name: ins
• Affected structure: pancreatic B cell
• Phenotype tag: abnormal
• Phenotype quality: increased area

Gene ontology

• Biological process: negative regulation of acute inflammatory response;glucose metabolic process;regulation of transcription, DNA-templated;regulation of cellular amino acid metabolic process;endoplasmic reticulum to Golgi vesicle-mediated transport;acute-phase response;G protein-coupled receptor signaling pathway;cell-cell signaling;positive regulation of cell population proliferation;insulin receptor signaling pathway;regulation of signaling receptor activity;positive regulation of gene expression;positive regulation of nitric oxide mediated signal transduction;positive regulation of phosphatidylinositol 3-kinase signaling;regulation of transmembrane transporter activity;positive regulation of cell growth;positive regulation of cell migration;positive regulation of protein autophosphorylation;activation of protein kinase B activity;positive regulation of cellular protein metabolic process;negative regulation of protein oligomerization;regulation of protein localization;negative regulation of NAD(P)H oxidase activity;wound healing;negative regulation of protein catabolic process;glucose homeostasis;positive regulation of MAPK cascade;cellular protein metabolic process;positive regulation of cell differentiation;negative regulation of gluconeogenesis;positive regulation of glycogen biosynthetic process;negative regulation of glycogen catabolic process;positive regulation of glycolytic process;positive regulation of mitotic nuclear division;negative regulation of proteolysis;negative regulation of fatty acid metabolic process;positive regulation of glucose import;positive regulation of insulin receptor signaling pathway;alpha-beta T cell activation;positive regulation of lipid biosynthetic process;regulation of synaptic plasticity;regulation of protein secretion;negative regulation of protein secretion;positive regulation of cytokine secretion;cognition;negative regulation of lipid catabolic process;positive regulation of nitric-oxide synthase activity;positive regulation of NF-kappaB transcription factor activity;positive regulation of protein kinase B signaling;fatty acid homeostasis;negative regulation of respiratory burst involved in inflammatory response;positive regulation of respiratory burst;positive regulation of peptide hormone secretion;positive regulation of brown fat cell differentiation;positive regulation of blood vessel diameter;negative regulation of blood vessel diameter;positive regulation of protein localization to nucleus;positive regulation of long-term synaptic potentiation;negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway;positive regulation of dendritic spine maintenance;regulation of protein localization to plasma membrane;negative regulation of reactive oxygen species biosynthetic process;neuron projection maintenance;negative regulation of feeding behavior
• Cellular component: Golgi membrane;extracellular region;extracellular space;endoplasmic reticulum lumen;Golgi lumen;transport vesicle;endosome lumen;endoplasmic reticulum-Golgi intermediate compartment membrane;secretory granule lumen
• Molecular function: protease binding;insulin receptor binding;insulin-like growth factor receptor binding;hormone activity;protein binding;identical protein binding