Type 1 diabetes mellitus 2

Summary

Type 1 diabetes mellitus 2 (MONDO:0007454) is a disease caused by INS (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: INS (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 31

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	type 1 diabetes mellitus 2
Mondo ID	MONDO:0007454
MeSH	C565100
OMIM	125852
DOID	DOID:0110741
UMLS	C1852092
MedGen	377588
Is cancer (heuristic)	no

Also known as: diabetes mellitus, insulin-dependent, type 2 · IDDM2 · INS type 1 diabetes mellitus · insulin-dependent diabetes mellitus 2 · type 1 diabetes mellitus caused by mutation in INS

Data availability: 31 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › diabetes mellitus, insulin-dependent, X-linked, susceptibility to › type 1 diabetes mellitus 2

Related subtypes (20): type 1 diabetes mellitus 1, type 1 diabetes mellitus 3, type 1 diabetes mellitus 4, type 1 diabetes mellitus 5, type 1 diabetes mellitus 7, type 1 diabetes mellitus 8, type 1 diabetes mellitus 11, type 1 diabetes mellitus 13, type 1 diabetes mellitus 12, type 1 diabetes mellitus 15, type 1 diabetes mellitus 6, type 1 diabetes mellitus 10, type 1 diabetes mellitus 17, type 1 diabetes mellitus 18, type 1 diabetes mellitus 19, type 1 diabetes mellitus 20, type 1 diabetes mellitus 21, type 1 diabetes mellitus 22, type 1 diabetes mellitus 23, type 1 diabetes mellitus 24

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

31 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 6 conflicting classifications of pathogenicity, 4 benign/likely benign, 4 pathogenic/likely pathogenic, 1 pathogenic/likely pathogenic/likely risk allele, 1 pathogenic, 1 likely pathogenic, 1 likely risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
13392	NM_000207.3(INS):c.163C>T (p.Arg55Cys)	INS	Pathogenic/Likely pathogenic/Likely risk allele	criteria provided, multiple submitters, no conflicts
1455986	NM_000207.3(INS):c.1A>G (p.Met1Val)	INS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21122	NM_000207.3(INS):c.94G>A (p.Gly32Ser)	INS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431442	NM_000207.3(INS):c.-152C>A	INS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431443	NM_000207.3(INS):c.-152C>G	INS	Pathogenic	criteria provided, multiple submitters, no conflicts
13380	NM_000207.3(INS):c.266G>A (p.Arg89His)	INS-IGF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
65581	NM_000207.3(INS):c.*59A>G	INS	Likely pathogenic	criteria provided, single submitter
918067	NM_000207.3(INS):c.286T>C (p.Cys96Arg)	INS-IGF2	Likely risk allele	criteria provided, single submitter
1317682	NM_000207.3(INS):c.-153C>G	INS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
304051	NM_000207.3(INS):c.*22A>C	INS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
68727	NM_000207.3(INS):c.17G>A (p.Arg6His)	INS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
730224	NM_000207.3(INS):c.67G>A (p.Ala23Thr)	INS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1049511	NM_000207.3(INS):c.227G>A (p.Ser76Asn)	INS-IGF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14451	NM_000236.3(LIPC):c.1214C>T (p.Thr405Met)	LIPC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2634300	NM_000207.3(INS):c.-152C>T	INS	Uncertain significance	criteria provided, multiple submitters, no conflicts
3364832	NM_000207.3(INS):c.35C>T (p.Ala12Val)	INS	Uncertain significance	criteria provided, multiple submitters, no conflicts
3599476	NM_000207.3(INS):c.208G>A (p.Gly70Arg)	INS	Uncertain significance	criteria provided, single submitter
3599477	NM_000207.3(INS):c.200A>T (p.Glu67Val)	INS	Uncertain significance	criteria provided, single submitter
3599478	NM_000207.3(INS):c.194A>T (p.Gln65Leu)	INS	Uncertain significance	criteria provided, single submitter
3599479	NM_000207.3(INS):c.188-16C>A	INS	Uncertain significance	criteria provided, single submitter
3599480	NM_000207.3(INS):c.187+3G>A	INS	Uncertain significance	criteria provided, multiple submitters, no conflicts
3599481	NM_000207.3(INS):c.170A>G (p.Glu57Gly)	INS	Uncertain significance	criteria provided, single submitter
3599483	NM_000207.3(INS):c.157A>G (p.Lys53Glu)	INS	Uncertain significance	criteria provided, single submitter
3599484	NM_000207.3(INS):c.44C>A (p.Ala15Asp)	INS	Uncertain significance	criteria provided, single submitter
304058	NM_000207.3(INS):c.25C>T (p.Pro9Ser)	INS-IGF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3599475	NM_000207.3(INS):c.212G>T (p.Gly71Val)	INS-IGF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3599482	NM_000207.3(INS):c.158A>C (p.Lys53Thr)	INS-IGF2	Uncertain significance	criteria provided, single submitter
129279	NM_000207.3(INS):c.188-10G>A	INS	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
255532	NM_000207.3(INS):c.187+11T>C	INS-IGF2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
304057	NM_000207.3(INS):c.36G>A (p.Ala12=)	INS-IGF2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
INS	Strong	Autosomal dominant	transient neonatal diabetes mellitus	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
INS	Orphanet:552	MODY
INS	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
LIPC	Orphanet:140905	Hyperlipidemia due to hepatic triacylglycerol lipase deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
INS	HGNC:6081	ENSG00000254647	P01308	Insulin	gencc,clinvar
INS-IGF2	HGNC:33527	ENSG00000129965	F8WCM5	Insulin, isoform 2	clinvar
LIPC	HGNC:6619	ENSG00000166035	P11150	Hepatic triacylglycerol lipase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
INS	Insulin	Insulin decreases blood glucose concentration.
LIPC	Hepatic triacylglycerol lipase	Catalyzes the hydrolysis of triglycerides and phospholipids present in circulating plasma lipoproteins, including chylomicrons, intermediate density lipoproteins (IDL), low density lipoproteins (LDL) of large size and high density lipoprot…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
INS	Other/Unknown	no		Insulin, Insulin-like, Ins/IGF/rlx
INS-IGF2	Other/Unknown	no		Insulin, Insulin-like, Insulin-like_sf
LIPC	Other/Unknown	no		TAG_lipase, PLAT/LH2_dom, Lipase_hep

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	1
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	2
islet of Langerhans	2
type B pancreatic cell	1
pancreas	1
colonic epithelium	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
INS	137	tissue_specific	marker	type B pancreatic cell, islet of Langerhans, body of pancreas
INS-IGF2	20	broad	marker	islet of Langerhans, pancreas, body of pancreas
LIPC	158	broad	marker	right lobe of liver, liver, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
INS	11,670
LIPC	1,603
INS-IGF2	1,005

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INS	P01308	382
INS-IGF2	F8WCM5	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LIPC	P11150	82.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 42. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
IRS activation	1	1142.0×	0.013	INS
Chylomicron clearance	1	1142.0×	0.013	LIPC
Signal attenuation	1	519.1×	0.013	INS
Signaling by Insulin receptor	1	439.2×	0.013	INS
Regulation of beta-cell development	1	356.9×	0.013	INS
Insulin receptor signalling cascade	1	335.9×	0.013	INS
Synthesis, secretion, and deacylation of Ghrelin	1	300.5×	0.013	INS
Assembly of active LPL and LIPC lipase complexes	1	300.5×	0.013	LIPC
Transcriptional Regulation by NPAS4	1	285.5×	0.013	INS
Regulation of gene expression in beta cells	1	259.6×	0.013	INS
NPAS4 regulates expression of target genes	1	248.3×	0.013	INS
Plasma lipoprotein remodeling	1	237.9×	0.013	LIPC
Plasma lipoprotein clearance	1	237.9×	0.013	LIPC
Insulin processing	1	228.4×	0.013	INS
Insulin receptor recycling	1	190.3×	0.014	INS
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	190.3×	0.014	INS
FOXO-mediated transcription	1	167.9×	0.015	INS
Negative regulation of the PI3K/AKT network	1	139.3×	0.016	INS
Peptide hormone metabolism	1	135.9×	0.016	INS
Plasma lipoprotein assembly, remodeling, and clearance	1	114.2×	0.018	LIPC
Regulation of insulin secretion	1	109.8×	0.018	INS
Integration of energy metabolism	1	87.8×	0.022	INS
ER to Golgi Anterograde Transport	1	66.4×	0.027	INS
COPI-mediated anterograde transport	1	54.9×	0.031	INS
Transport to the Golgi and subsequent modification	1	51.4×	0.031	INS
Amyloid fiber formation	1	51.4×	0.031	INS
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	48.4×	0.032	INS
Intracellular signaling by second messengers	1	45.7×	0.033	INS
PIP3 activates AKT signaling	1	33.4×	0.043	INS
Asparagine N-linked glycosylation	1	30.1×	0.046	INS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intermediate-density lipoprotein particle remodeling	1	8426.0×	0.004	LIPC
negative regulation of glycogen catabolic process	1	4213.0×	0.004	INS
positive regulation of nitric-oxide synthase activity	1	2808.7×	0.004	INS
obsolete positive regulation of nitric oxide mediated signal transduction	1	2106.5×	0.004	INS
negative regulation of fatty acid metabolic process	1	2106.5×	0.004	INS
negative regulation of feeding behavior	1	2106.5×	0.004	INS
alpha-beta T cell activation	1	1685.2×	0.004	INS
negative regulation of respiratory burst involved in inflammatory response	1	1685.2×	0.004	INS
positive regulation of respiratory burst	1	1685.2×	0.004	INS
positive regulation of dendritic spine maintenance	1	1685.2×	0.004	INS
chylomicron remnant clearance	1	1404.3×	0.004	LIPC
negative regulation of acute inflammatory response	1	1203.7×	0.005	INS
very-low-density lipoprotein particle remodeling	1	1053.2×	0.005	LIPC
nitric oxide-cGMP-mediated signaling	1	766.0×	0.005	INS
regulation of protein secretion	1	766.0×	0.005	INS
positive regulation of peptide hormone secretion	1	766.0×	0.005	INS
phosphatidylcholine catabolic process	1	648.1×	0.005	LIPC
neuron projection maintenance	1	561.7×	0.005	INS
low-density lipoprotein particle remodeling	1	526.6×	0.005	LIPC
positive regulation of glycogen biosynthetic process	1	495.6×	0.005	INS
positive regulation of brown fat cell differentiation	1	495.6×	0.005	INS
negative regulation of reactive oxygen species biosynthetic process	1	495.6×	0.005	INS
reverse cholesterol transport	1	468.1×	0.005	LIPC
fatty acid homeostasis	1	468.1×	0.005	INS
negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1	468.1×	0.005	INS
positive regulation of lipid biosynthetic process	1	443.5×	0.005	INS
negative regulation of protein secretion	1	443.5×	0.005	INS
positive regulation of insulin receptor signaling pathway	1	421.3×	0.005	INS
negative regulation of lipid catabolic process	1	421.3×	0.005	INS
triglyceride catabolic process	1	401.2×	0.005	LIPC

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
LIPC	ORLISTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LIPC	1	4
INS	0	0
INS-IGF2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ORLISTAT	4	LIPC

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
LIPC	12	Binding:11, ADMET:1
INS	8	Binding:7, ADMET:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ORLISTAT	4	LIPC

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LIPC
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	INS, INS-IGF2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
INS	8	—
INS-IGF2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.