Type 1 diabetes mellitus 20

Summary

Type 1 diabetes mellitus 20 (MONDO:0012919) is a disease caused by HNF1A (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: HNF1A (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 165

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	type 1 diabetes mellitus 20
Mondo ID	MONDO:0012919
MeSH	C567286
OMIM	612520
DOID	DOID:0110757
UMLS	C2675866
MedGen	382706
Is cancer (heuristic)	no

Also known as: diabetes mellitus, insulin-dependent, 20 · diabetes mellitus, insulin-dependent, type 20 · HNF1A type 1 diabetes mellitus · IDDM20 · type 1 diabetes mellitus caused by mutation in HNF1A

Data availability: 165 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 20

Related subtypes (20): type 1 diabetes mellitus 2, 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 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

165 retrieved; paginated sample, class counts are floors:

83 uncertain significance, 27 conflicting classifications of pathogenicity, 15 pathogenic, 10 likely pathogenic, 9 benign, 8 likely benign, 7 benign/likely benign, 5 uncertain significance/uncertain risk allele, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033090	NM_000545.8(HNF1A):c.58G>A (p.Gly20Arg)	HNF1A	Pathogenic	reviewed by expert panel
1328238	NM_000545.8(HNF1A):c.863_864insC (p.Pro289fs)	HNF1A	Pathogenic	criteria provided, multiple submitters, no conflicts
14927	NM_000545.8(HNF1A):c.872dup (p.Gly292fs)	HNF1A	Pathogenic	reviewed by expert panel
14928	NM_000545.8(HNF1A):c.1340C>T (p.Pro447Leu)	HNF1A	Pathogenic	reviewed by expert panel
14931	NM_000545.8(HNF1A):c.815G>A (p.Arg272His)	HNF1A	Pathogenic	reviewed by expert panel
14938	NM_000545.8(HNF1A):c.142del (p.Glu48fs)	HNF1A	Pathogenic	reviewed by expert panel
1693221	NM_000545.8(HNF1A):c.1556C>T (p.Pro519Leu)	HNF1A	Pathogenic	reviewed by expert panel
1803148	NM_000545.8(HNF1A):c.1522G>T (p.Glu508Ter)	HNF1A	Pathogenic	criteria provided, single submitter
3574303	NM_000545.8(HNF1A):c.1456C>T (p.Gln486Ter)	HNF1A	Pathogenic	criteria provided, single submitter
36824	NM_000545.5(HNF1A):c.598C>T (p.Arg200Trp)	HNF1A	Pathogenic	reviewed by expert panel
372380	NM_000545.8(HNF1A):c.526C>T (p.Gln176Ter)	HNF1A	Pathogenic	reviewed by expert panel
379138	NM_000545.8(HNF1A):c.788G>A (p.Arg263His)	HNF1A	Pathogenic	reviewed by expert panel
420064	NM_000545.8(HNF1A):c.685C>T (p.Arg229Ter)	HNF1A	Pathogenic	reviewed by expert panel
447503	NM_000545.8(HNF1A):c.814C>T (p.Arg272Cys)	HNF1A	Pathogenic	reviewed by expert panel
562373	NM_000545.8(HNF1A):c.392G>A (p.Arg131Gln)	HNF1A	Pathogenic	reviewed by expert panel
817605	NM_000545.8(HNF1A):c.864delinsCC (p.Gly292fs)	HNF1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179147	NM_000545.8(HNF1A):c.1310-2A>G	HNF1A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3574277	NM_000545.8(HNF1A):c.-64_-55delinsGC	HNF1A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3574278	NM_000545.8(HNF1A):c.3G>A (p.Met1Ile)	HNF1A	Likely pathogenic	criteria provided, single submitter
3574308	NM_000545.8(HNF1A):c.1555_1556dup (p.Gln520fs)	HNF1A	Likely pathogenic	criteria provided, single submitter
3574309	NM_000545.8(HNF1A):c.1575_1576delinsA (p.Asp526fs)	HNF1A	Likely pathogenic	criteria provided, single submitter
3574311	NM_000545.8(HNF1A):c.1715del (p.Pro572fs)	HNF1A	Likely pathogenic	criteria provided, single submitter
3574313	NM_000545.8(HNF1A):c.1720delinsGGCATCCAGCACCG (p.Ser574fs)	HNF1A	Likely pathogenic	criteria provided, single submitter
36832	NM_000545.8(HNF1A):c.827C>G (p.Ala276Gly)	HNF1A	Likely pathogenic	reviewed by expert panel
430837	NM_000545.8(HNF1A):c.1501+1G>A	HNF1A	Likely pathogenic	reviewed by expert panel
435424	NM_000545.8(HNF1A):c.864del (p.Pro291fs)	HNF1A	Likely pathogenic	reviewed by expert panel
994545	NM_000545.8(HNF1A):c.1769T>C (p.Val590Ala)	C12orf43	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
402948	NM_000545.8(HNF1A):c.923C>T (p.Pro308Leu)	HNF1A	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
882514	NM_000545.8(HNF1A):c.1727A>C (p.Gln576Pro)	HNF1A	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
884166	NM_000545.8(HNF1A):c.499G>A (p.Val167Ile)	HNF1A	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 12 · 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
HNF1A	Definitive	Autosomal dominant	monogenic diabetes	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HNF1A	Orphanet:319303	Chromophobe renal cell carcinoma
HNF1A	Orphanet:324575	Hyperinsulinism due to HNF1A deficiency
HNF1A	Orphanet:404511	Clear cell papillary renal cell carcinoma
HNF1A	Orphanet:552	MODY
KCNJ11	Orphanet:276580	Autosomal dominant hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:276603	Diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:552	MODY
KCNJ11	Orphanet:79134	DEND syndrome
KCNJ11	Orphanet:79644	Autosomal recessive hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
KCNJ11	Orphanet:99886	Transient neonatal diabetes mellitus
KCNJ11	Orphanet:99989	Intermediate DEND syndrome

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
HNF1A	HGNC:11621	ENSG00000135100	P20823	Hepatocyte nuclear factor 1-alpha	gencc,clinvar
C12orf43	HGNC:25719	ENSG00000157895	Q96C57	Protein CUSTOS	clinvar
KCNJ11	HGNC:6257	ENSG00000187486	Q14654	ATP-sensitive inward rectifier potassium channel 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HNF1A	Hepatocyte nuclear factor 1-alpha	Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver.
C12orf43	Protein CUSTOS	Plays a role in the regulation of Wnt signaling pathway during early development.
KCNJ11	ATP-sensitive inward rectifier potassium channel 11	Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Ion channel	1	37.2×	0.080
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HNF1A	Transcription factor	no		HD, HNF1b_C, HNF1a_C
C12orf43	Other/Unknown	no		CUSTOS
KCNJ11	Ion channel	yes		K_chnl_inward-rec_Kir6.2, K_chnl_inward-rec_Kir_cyto, Ig_E-set

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
mucosa of transverse colon	1
right lobe of liver	1
oocyte	1
prefrontal cortex	1
secondary oocyte	1
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HNF1A	81	tissue_specific	yes	right lobe of liver, mucosa of transverse colon, liver
C12orf43	266	ubiquitous	marker	secondary oocyte, oocyte, prefrontal cortex
KCNJ11	161	broad	yes	gastrocnemius, hindlimb stylopod muscle, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNF1A	2,491
KCNJ11	1,715
C12orf43	621

Intra-cohort edges

A	B	Sources
HNF1A	KCNJ11	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNJ11	Q14654	9
HNF1A	P20823	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C12orf43	Q96C57	64.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	2855.0×	0.003	KCNJ11
Defective ABCC8 can cause hypo- and hyper-glycemias	1	2855.0×	0.003	KCNJ11
ATP sensitive Potassium channels	1	1427.5×	0.004	KCNJ11
Inwardly rectifying K+ channels	1	356.9×	0.013	KCNJ11
Regulation of gene expression in beta cells	1	259.6×	0.014	HNF1A
ABC transporter disorders	1	219.6×	0.014	KCNJ11
Regulation of insulin secretion	1	109.8×	0.022	KCNJ11
Ion homeostasis	1	102.0×	0.022	KCNJ11
Integration of energy metabolism	1	87.8×	0.023	KCNJ11
Disorders of transmembrane transporters	1	69.6×	0.024	KCNJ11
Potassium Channels	1	67.2×	0.024	KCNJ11
ABC-family protein mediated transport	1	60.7×	0.025	KCNJ11
Cardiac conduction	1	54.4×	0.025	KCNJ11
Muscle contraction	1	38.6×	0.033	KCNJ11
Neuronal System	1	22.1×	0.054	KCNJ11
Transport of small molecules	1	12.6×	0.088	KCNJ11
Disease	1	6.5×	0.156	KCNJ11
Metabolism	1	5.8×	0.165	KCNJ11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
renal D-glucose absorption	1	1872.4×	0.009	HNF1A
Spemann organizer formation	1	1872.4×	0.009	C12orf43
response to resveratrol	1	1123.5×	0.009	KCNJ11
CAMKK-AMPK signaling cascade	1	936.2×	0.009	KCNJ11
ventricular cardiac muscle tissue development	1	702.2×	0.009	KCNJ11
nervous system process	1	401.2×	0.013	KCNJ11
response to ATP	1	330.4×	0.013	KCNJ11
obsolete inorganic cation transmembrane transport	1	312.1×	0.013	KCNJ11
obsolete D-glucose import	1	280.9×	0.013	HNF1A
regulation of monoatomic ion transmembrane transport	1	244.2×	0.013	KCNJ11
pancreas development	1	224.7×	0.013	HNF1A
negative regulation of insulin secretion	1	165.2×	0.015	KCNJ11
cellular response to nutrient levels	1	156.0×	0.015	KCNJ11
determination of adult lifespan	1	144.0×	0.015	KCNJ11
insulin secretion	1	144.0×	0.015	HNF1A
regulation of insulin secretion	1	130.6×	0.015	KCNJ11
potassium ion import across plasma membrane	1	122.1×	0.015	KCNJ11
action potential	1	119.5×	0.015	KCNJ11
negative regulation of Wnt signaling pathway	1	114.6×	0.015	C12orf43
positive regulation of transcription initiation by RNA polymerase II	1	90.6×	0.018	HNF1A
glucose metabolic process	1	85.1×	0.018	KCNJ11
response to ischemia	1	83.8×	0.018	KCNJ11
regulation of membrane potential	1	77.0×	0.019	KCNJ11
liver development	1	73.9×	0.019	HNF1A
potassium ion transmembrane transport	1	45.3×	0.029	KCNJ11
glucose homeostasis	1	43.5×	0.029	HNF1A
Wnt signaling pathway	1	33.2×	0.036	C12orf43
response to hypoxia	1	31.9×	0.037	KCNJ11
response to xenobiotic stimulus	1	23.0×	0.049	KCNJ11
apoptotic process	1	9.6×	0.110	KCNJ11

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
KCNJ11	PINACIDIL ANHYDROUS

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNJ11	7	4
HNF1A	0	0
C12orf43	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PINACIDIL ANHYDROUS	4	KCNJ11
GLYBURIDE	4	KCNJ11
PROPAFENONE	4	KCNJ11
DIAZOXIDE	4	KCNJ11
CROMAKALIM	2	KCNJ11
CLAMIKALANT	2	KCNJ11
TIFENAZOXIDE	2	KCNJ11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNJ11	102	Functional:59, Binding:43
HNF1A	1	Binding:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
KCNJ11	102

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

7 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)
PINACIDIL ANHYDROUS	4	KCNJ11
GLYBURIDE	4	KCNJ11
PROPAFENONE	4	KCNJ11
DIAZOXIDE	4	KCNJ11
CROMAKALIM	2	KCNJ11
CLAMIKALANT	2	KCNJ11
TIFENAZOXIDE	2	KCNJ11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNJ11
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	HNF1A, C12orf43

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)
HNF1A	1	—
C12orf43	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.