Diabetes mellitus, permanent neonatal 4

Summary

Diabetes mellitus, permanent neonatal 4 (MONDO:0030089) is a disease caused by INS (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: INS (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 48

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diabetes mellitus, permanent neonatal 4
Mondo ID	MONDO:0030089
OMIM	618858
UMLS	C5394307
MedGen	1711191
GARD	0016390
Is cancer (heuristic)	no

Also known as: DIABETES MELLITUS, PERMANENT NEONATAL 4 · diabetes mellitus, permanent neonatal 4 · PNDM4

Data availability: 48 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › pancreas disorder › endocrine pancreas disorder › diabetes mellitus › monogenic diabetes › neonatal diabetes mellitus › permanent neonatal diabetes mellitus › diabetes mellitus, permanent neonatal 4

Related subtypes (4): DEND syndrome, diabetes mellitus, permanent neonatal 2, diabetes mellitus, permanent neonatal 3, permanent neonatal diabetes mellitus 1

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

48 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 8 conflicting classifications of pathogenicity, 5 benign/likely benign, 5 pathogenic/likely pathogenic, 3 pathogenic/likely risk allele, 3 likely risk allele, 2 likely pathogenic, 1 likely pathogenic/likely risk allele, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13388	NM_000207.3(INS):c.71C>A (p.Ala24Asp)	INS	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
21117	NM_000207.3(INS):c.265C>T (p.Arg89Cys)	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
21114	NM_000207.3(INS):c.127T>G (p.Cys43Gly)	INS-IGF2	Pathogenic/Likely risk allele	criteria provided, multiple submitters, no conflicts
211186	NM_000207.3(INS):c.188-31G>A	INS-IGF2	Pathogenic/Likely risk allele	criteria provided, multiple submitters, no conflicts
3393374	NM_000207.3(INS):c.283T>C (p.Cys95Arg)	INS	Likely pathogenic	criteria provided, single submitter
65581	NM_000207.3(INS):c.*59A>G	INS	Likely pathogenic	criteria provided, single submitter
13389	NM_000207.3(INS):c.143T>G (p.Phe48Cys)	INS-IGF2	Likely pathogenic/Likely risk allele	criteria provided, multiple submitters, no conflicts
21120	NM_000207.3(INS):c.323A>G (p.Tyr108Cys)	INS	Likely risk allele	criteria provided, single submitter
2664354	NM_000207.3(INS):c.104T>A (p.Leu35Gln)	INS	Likely risk allele	criteria provided, single submitter
68731	NM_000207.3(INS):c.302C>G (p.Ser101Cys)	INS	Likely risk allele	criteria provided, single submitter
1317682	NM_000207.3(INS):c.-153C>G	INS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13387	NM_000207.3(INS):c.287G>A (p.Cys96Tyr)	INS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
268153	NM_000207.3(INS):c.187+241G>A	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
13391	NM_000207.3(INS):c.137G>A (p.Arg46Gln)	INS-IGF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
68732	NM_000207.3(INS):c.308A>G (p.Tyr103Cys)	INS-IGF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
21115	NM_000207.3(INS):c.140G>T (p.Gly47Val)	INS	Uncertain significance	criteria provided, single submitter
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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 2 · 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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

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

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
INS	Insulin	Insulin decreases blood glucose concentration.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

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

Expression context

Cohort genes with no expression data: 0.

2 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	2
islet of Langerhans	2
type B pancreatic cell	1
pancreas	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

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

Structural data

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

Cohort genes with PDB structures (top 30)

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

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 36. Enrichment computed across 2 evidence-associated genes (1 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 1 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	2284.0×	0.008	INS
Signal attenuation	1	1038.2×	0.008	INS
Signaling by Insulin receptor	1	878.5×	0.008	INS
Regulation of beta-cell development	1	713.8×	0.008	INS
Insulin receptor signalling cascade	1	671.8×	0.008	INS
Synthesis, secretion, and deacylation of Ghrelin	1	601.0×	0.008	INS
Transcriptional Regulation by NPAS4	1	571.0×	0.008	INS
Regulation of gene expression in beta cells	1	519.1×	0.008	INS
NPAS4 regulates expression of target genes	1	496.5×	0.008	INS
Insulin processing	1	456.8×	0.008	INS
Insulin receptor recycling	1	380.7×	0.008	INS
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	380.7×	0.008	INS
FOXO-mediated transcription	1	335.9×	0.008	INS
Negative regulation of the PI3K/AKT network	1	278.5×	0.009	INS
Peptide hormone metabolism	1	271.9×	0.009	INS
Regulation of insulin secretion	1	219.6×	0.010	INS
Integration of energy metabolism	1	175.7×	0.012	INS
ER to Golgi Anterograde Transport	1	132.8×	0.015	INS
COPI-mediated anterograde transport	1	109.8×	0.017	INS
Transport to the Golgi and subsequent modification	1	102.9×	0.017	INS
Amyloid fiber formation	1	102.9×	0.017	INS
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.017	INS
Intracellular signaling by second messengers	1	91.4×	0.017	INS
PIP3 activates AKT signaling	1	66.8×	0.022	INS
Asparagine N-linked glycosylation	1	60.1×	0.024	INS
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.027	INS
Membrane Trafficking	1	37.1×	0.036	INS
Vesicle-mediated transport	1	34.8×	0.037	INS
RNA Polymerase II Transcription	1	22.5×	0.055	INS
Post-translational protein modification	1	19.2×	0.063	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of glycogen catabolic process	1	8426.0×	0.002	INS
positive regulation of nitric-oxide synthase activity	1	5617.3×	0.002	INS
obsolete positive regulation of nitric oxide mediated signal transduction	1	4213.0×	0.002	INS
negative regulation of fatty acid metabolic process	1	4213.0×	0.002	INS
negative regulation of feeding behavior	1	4213.0×	0.002	INS
alpha-beta T cell activation	1	3370.4×	0.002	INS
negative regulation of respiratory burst involved in inflammatory response	1	3370.4×	0.002	INS
positive regulation of respiratory burst	1	3370.4×	0.002	INS
positive regulation of dendritic spine maintenance	1	3370.4×	0.002	INS
negative regulation of acute inflammatory response	1	2407.4×	0.002	INS
nitric oxide-cGMP-mediated signaling	1	1532.0×	0.003	INS
regulation of protein secretion	1	1532.0×	0.003	INS
positive regulation of peptide hormone secretion	1	1532.0×	0.003	INS
neuron projection maintenance	1	1123.5×	0.003	INS
positive regulation of glycogen biosynthetic process	1	991.3×	0.003	INS
positive regulation of brown fat cell differentiation	1	991.3×	0.003	INS
negative regulation of reactive oxygen species biosynthetic process	1	991.3×	0.003	INS
fatty acid homeostasis	1	936.2×	0.003	INS
negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1	936.2×	0.003	INS
positive regulation of lipid biosynthetic process	1	887.0×	0.003	INS
negative regulation of protein secretion	1	887.0×	0.003	INS
positive regulation of insulin receptor signaling pathway	1	842.6×	0.003	INS
negative regulation of lipid catabolic process	1	842.6×	0.003	INS
negative regulation of gluconeogenesis	1	802.5×	0.003	INS
positive regulation of glycolytic process	1	674.1×	0.003	INS
positive regulation of long-term synaptic potentiation	1	674.1×	0.003	INS
regulation of protein localization to plasma membrane	1	648.1×	0.003	INS
positive regulation of mitotic nuclear division	1	543.6×	0.004	INS
positive regulation of D-glucose import across plasma membrane	1	455.5×	0.004	INS
acute-phase response	1	421.3×	0.004	INS

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
INS	0	0
INS-IGF2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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.