Diabetes mellitus, permanent neonatal 3

Summary

Diabetes mellitus, permanent neonatal 3 (MONDO:0030088) is a disease caused by ABCC8 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ABCC8 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 399

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diabetes mellitus, permanent neonatal 3
Mondo ID	MONDO:0030088
OMIM	618857
UMLS	C5394303
MedGen	1717271
GARD	0016389
Is cancer (heuristic)	no

Also known as: PNDM3

Data availability: 399 ClinVar variants · 4 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 3

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

399 retrieved; paginated sample, class counts are floors:

176 uncertain significance, 84 conflicting classifications of pathogenicity, 51 pathogenic/likely pathogenic, 33 likely benign, 23 pathogenic, 22 likely pathogenic, 6 benign, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071311	NM_000352.6(ABCC8):c.1332G>T (p.Gln444His)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076249	NM_000352.6(ABCC8):c.1647del (p.Ile550fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179142	NM_000352.6(ABCC8):c.1893del (p.Gln632fs)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1338472	NM_000352.6(ABCC8):c.2473C>T (p.Arg825Trp)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1338676	NM_000352.6(ABCC8):c.805del (p.Ala269fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1390642	NM_000352.6(ABCC8):c.45C>G (p.Tyr15Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457730	NM_000352.6(ABCC8):c.3988+2T>C	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459964	NM_000352.6(ABCC8):c.502C>T (p.Arg168Cys)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1506182	NM_000352.6(ABCC8):c.4544C>T (p.Thr1515Met)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
157696	NM_000352.6(ABCC8):c.3509del (p.Leu1170fs)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
188836	NM_000352.6(ABCC8):c.4628T>C (p.Leu1543Pro)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188864	NM_000352.6(ABCC8):c.2797C>T (p.Arg933Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188894	NM_000352.6(ABCC8):c.3124_3126delinsCAGCCAGGAACTG (p.Thr1042fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188905	NM_000352.6(ABCC8):c.2857C>T (p.Gln953Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188915	NM_000352.6(ABCC8):c.2506C>T (p.Arg836Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188931	NM_000352.6(ABCC8):c.4411G>A (p.Asp1471Asn)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
196880	NM_000352.6(ABCC8):c.4160_4162del (p.Phe1387del)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
210074	NM_000352.6(ABCC8):c.331G>A (p.Gly111Arg)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
210076	NM_000352.6(ABCC8):c.3544C>T (p.Arg1182Trp)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
210082	NM_000352.6(ABCC8):c.563A>G (p.Asn188Ser)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137013	NM_000352.6(ABCC8):c.2694+1G>A	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137021	NM_000352.6(ABCC8):c.1A>G (p.Met1Val)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217846	NM_000352.6(ABCC8):c.683G>A (p.Gly228Asp)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2418967	NM_000352.6(ABCC8):c.4177C>T (p.Arg1393Cys)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2576216	NM_000352.6(ABCC8):c.148+1G>A	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677316	NM_000352.6(ABCC8):c.4238C>T (p.Pro1413Leu)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2848441	NM_000352.6(ABCC8):c.4661G>T (p.Gly1554Val)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2855342	NM_000352.6(ABCC8):c.2004del (p.Ser669fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
35616	NM_000352.6(ABCC8):c.4198G>A (p.Gly1400Arg)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
35617	NM_000352.6(ABCC8):c.4306C>T (p.Arg1436Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 32 · Orphanet: 7 · 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
ABCC8	Definitive	Semidominant	diabetes mellitus	32

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ABCC8	Orphanet:276575	Autosomal dominant hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:276598	Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:552	MODY
ABCC8	Orphanet:79134	DEND syndrome
ABCC8	Orphanet:79643	Autosomal recessive hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
ABCC8	Orphanet:99886	Transient neonatal diabetes mellitus

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ABCC8	ATP-binding cassette sub-family C member 8	Regulator subunit of pancreatic ATP-sensitive potassium channel (KATP), playing a major role in the regulation of insulin release.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ABCC8	Transporter	yes		ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	1
islet of Langerhans	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ABCC8	185	broad	marker	islet of Langerhans, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCC8	2,826

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCC8	Q09428	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 1 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
Defective ABCC8 can cause hypo- and hyper-glycemias	1	5710.0×	0.002	ABCC8
ATP sensitive Potassium channels	1	2855.0×	0.002	ABCC8
Inwardly rectifying K+ channels	1	713.8×	0.005	ABCC8
ABC transporter disorders	1	439.2×	0.006	ABCC8
Regulation of insulin secretion	1	219.6×	0.010	ABCC8
Integration of energy metabolism	1	175.7×	0.010	ABCC8
Disorders of transmembrane transporters	1	139.3×	0.010	ABCC8
Potassium Channels	1	134.3×	0.010	ABCC8
Neuronal System	1	44.3×	0.028	ABCC8
Disease	1	13.1×	0.084	ABCC8
Metabolism	1	11.6×	0.086	ABCC8

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 neuroblast migration	1	16852.0×	9e-04	ABCC8
positive regulation of uterine smooth muscle relaxation	1	16852.0×	9e-04	ABCC8
glutamate secretion, neurotransmission	1	5617.3×	0.001	ABCC8
negative regulation of blood-brain barrier permeability	1	5617.3×	0.001	ABCC8
positive regulation of tight junction disassembly	1	3370.4×	0.002	ABCC8
response to pH	1	2808.7×	0.002	ABCC8
positive regulation of potassium ion transport	1	2106.5×	0.002	ABCC8
negative regulation of glial cell proliferation	1	1685.2×	0.002	ABCC8
negative regulation of low-density lipoprotein particle clearance	1	1532.0×	0.002	ABCC8
obsolete inorganic cation transmembrane transport	1	936.2×	0.003	ABCC8
response to zinc ion	1	624.1×	0.004	ABCC8
intracellular glucose homeostasis	1	581.1×	0.004	ABCC8
neuromuscular process	1	526.6×	0.004	ABCC8
negative regulation of insulin secretion	1	495.6×	0.004	ABCC8
cellular response to nutrient levels	1	468.1×	0.004	ABCC8
regulation of insulin secretion	1	391.9×	0.004	ABCC8
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	374.5×	0.004	ABCC8
potassium ion import across plasma membrane	1	366.4×	0.004	ABCC8
action potential	1	358.6×	0.004	ABCC8
visual learning	1	306.4×	0.005	ABCC8
response to insulin	1	230.8×	0.006	ABCC8
female pregnancy	1	210.7×	0.006	ABCC8
potassium ion transport	1	191.5×	0.007	ABCC8
memory	1	183.2×	0.007	ABCC8
negative regulation of angiogenesis	1	168.5×	0.007	ABCC8
transmembrane transport	1	168.5×	0.007	ABCC8
positive regulation of tumor necrosis factor production	1	153.2×	0.007	ABCC8
potassium ion transmembrane transport	1	135.9×	0.008	ABCC8
response to lipopolysaccharide	1	124.8×	0.008	ABCC8
response to xenobiotic stimulus	1	69.1×	0.014	ABCC8

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
ABCC8	REPAGLINIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCC8	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
REPAGLINIDE	4	ABCC8
DIAZOXIDE	4	ABCC8
GLYBURIDE	4	ABCC8
CROMAKALIM	2	ABCC8
CLAMIKALANT	2	ABCC8
TIFENAZOXIDE	2	ABCC8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ABCC8	84	Functional:52, Binding:32

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

6 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)
REPAGLINIDE	4	ABCC8
DIAZOXIDE	4	ABCC8
GLYBURIDE	4	ABCC8
CROMAKALIM	2	ABCC8
CLAMIKALANT	2	ABCC8
TIFENAZOXIDE	2	ABCC8

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ABCC8
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.