Diabetes insipidus

Summary

Diabetes insipidus (MONDO:0004782) is a disease with 3 cohort genes and 16 clinical trials. Top therapeutic interventions include desmopressin, carboplatin, and chlorpropamide.

At a glance

• Cohort genes: 3
• ClinVar variants: 3
• Clinical trials: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diabetes insipidus
Mondo ID	MONDO:0004782
MeSH	D003919
DOID	DOID:9409
ICD-10-CM	E23.2
NCIT	C43263
SNOMED CT	15771004
UMLS	C0011848
MedGen	8349
Is cancer (heuristic)	no

Data availability: 3 ClinVar variants.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › diabetes insipidus

Related subtypes (56): renal hypertension, kidney failure, nephritis, impaired renal function disease, nephrocalcinosis, atheroembolism of kidney, renal artery disease, nephrosis, cystic kidney disease, anuria, stricture or kinking of ureter, proteinuria, renal infectious disease, orthostatic proteinuria, kidney hypertrophy, chronic kidney disease, hydronephrosis, renal tubular transport disease, kidney cortex necrosis, kidney papillary necrosis, perinephritis, renal aminoaciduria, autosomal dominant progressive nephropathy with hypertension, nephrolithiasis, X-linked diffuse leiomyomatosis-Alport syndrome, tubulointerstitial nephritis and uveitis syndrome, distal renal tubular acidosis, oligomeganephronia, duplication of urethra, renal tubular dysgenesis, exstrophy-epispadias complex, fetal lower urinary tract obstruction, IgG4-related kidney disease, congenital primary megaureter, renal nutcracker syndrome, renal hypoplasia, renal dysplasia, congenital megacalycosis, glomerular disorder, congenital renal artery stenosis, kidney neoplasm, renal tubule disorder, pyonephrosis, Arnold stickler bourne syndrome, C1q nephropathy, hypertensive nephropathy, atypical Fanconi syndrome-neonatal hyperinsulinism syndrome, idiopathic non-lupus full-house nephropathy, lachiewicz sibley syndrome, crush syndrome, obstructive nephropathy, inherited kidney disorder, acute tubulointerstitial nephritis, kidney cortex disease, non-syndromic supernumerary kidneys, neonatal renal venous thrombosis

Subtypes (4): neurohypophyseal diabetes insipidus, nephrogenic diabetes insipidus, dipsogenic diabetes insipidus, gestational diabetes insipidus

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

3 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
17833	NM_000486.6(AQP2):c.377C>T (p.Thr126Met)	AQP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183295	NM_001393530.1(MATN4):c.515G>C (p.Gly172Ala)	MATN4	Likely pathogenic	no assertion criteria provided
383370	NM_000490.5(AVP):c.329G>A (p.Cys110Tyr)	AVP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AQP2	Orphanet:223	Arginine vasopressin resistance
AVP	Orphanet:30925	Hereditary arginine vasopressin 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
AQP2	HGNC:634	ENSG00000167580	P41181	Aquaporin-2	clinvar
MATN4	HGNC:6910	ENSG00000124159	O95460	Matrilin-4	clinvar
AVP	HGNC:894	ENSG00000101200	P01185	Vasopressin-neurophysin 2-copeptin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AQP2	Aquaporin-2	Forms a water-specific channel that provides the plasma membranes of renal collecting duct with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient.
MATN4	Matrilin-4	Major component of the extracellular matrix of cartilage.
AVP	Vasopressin-neurophysin 2-copeptin	Has a direct antidiuretic action on the kidney, it also causes vasoconstriction of the peripheral vessels.

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)
AQP2	Other/Unknown	no		MIP, MIP_CS, Aquaporin-like
MATN4	Other/Unknown	no		EGF, EGF-like_Ca-bd_dom, VWF_A
AVP	Other/Unknown	no		Neurhyp_horm, Neurohypophysial_hormone_CS, Neurhyp_horm_dom_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)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	2
metanephros cortex	1
renal medulla	1
seminal vesicle	1
body of pancreas	1
cartilage tissue	1
hypothalamus	1
ileal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AQP2	101	tissue_specific	marker	renal medulla, metanephros cortex, seminal vesicle
MATN4	96	tissue_specific	yes	cartilage tissue, body of pancreas, buccal mucosa cell
AVP	125	tissue_specific	marker	hypothalamus, ileal mucosa, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AQP2	3,471
AVP	2,070
MATN4	1,168

Intra-cohort edges

A	B	Sources
AQP2	AVP	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AQP2	P41181	7
AVP	P01185	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MATN4	O95460	82.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Aquaporin-mediated transport	2	245.6×	6e-04	AQP2, AVP
Vasopressin regulates renal water homeostasis via Aquaporins	2	177.1×	6e-04	AQP2, AVP
Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI)	1	1903.3×	0.005	AVP
Defective AVP does not bind AVPR1A,B and causes neurohypophyseal diabetes insipidus (NDI)	1	1268.9×	0.006	AVP
Vasopressin-like receptors	1	634.4×	0.009	AVP
Organic anion transport by SLCO transporters	1	346.1×	0.014	AVP
Passive transport by Aquaporins	1	292.8×	0.014	AQP2
Transport of small molecules	2	16.8×	0.017	AQP2, AVP
BMAL1:CLOCK,NPAS2 activates circadian expression	1	141.0×	0.023	AVP
R-HSA-400253	1	115.3×	0.025	AVP
Transport of vitamins, nucleosides, and related molecules	1	90.6×	0.029	AVP
SLC transporter disorders	1	68.0×	0.035	AVP
ECM proteoglycans	1	50.1×	0.044	MATN4
Disorders of transmembrane transporters	1	46.4×	0.044	AVP
Cargo recognition for clathrin-mediated endocytosis	1	34.9×	0.055	AVP
Clathrin-mediated endocytosis	1	28.4×	0.062	AVP
Class A/1 (Rhodopsin-like receptors)	1	24.7×	0.062	AVP
Peptide ligand-binding receptors	1	24.7×	0.062	AVP
G alpha (s) signalling events	1	24.4×	0.062	AVP
GPCR ligand binding	1	21.4×	0.065	AVP
Extracellular matrix organization	1	21.0×	0.065	MATN4
SLC-mediated transmembrane transport	1	19.7×	0.065	AVP
G alpha (q) signalling events	1	19.1×	0.065	AVP
GPCR downstream signalling	1	14.5×	0.082	AVP
Signaling by GPCR	1	13.4×	0.085	AVP
Membrane Trafficking	1	12.4×	0.088	AVP
Vesicle-mediated transport	1	11.6×	0.090	AVP
Disease	1	4.4×	0.220	AVP
Signal Transduction	1	3.4×	0.267	AVP

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
water transport	2	660.9×	1e-04	AQP2, AVP
renal water transport	1	1872.4×	0.004	AQP2
cellular response to water deprivation	1	1872.4×	0.004	AQP2
cellular response to mercury ion	1	1872.4×	0.004	AQP2
response to nerve growth factor	1	1872.4×	0.004	AVP
maternal aggressive behavior	1	1404.3×	0.004	AVP
obsolete positive regulation of cellular pH reduction	1	1404.3×	0.004	AVP
negative regulation of female receptivity	1	1123.5×	0.004	AVP
response to 2,3,7,8-tetrachlorodibenzodioxine	1	1123.5×	0.004	AVP
positive regulation of glutamate secretion	1	802.5×	0.005	AVP
negative regulation of transmission of nerve impulse	1	802.5×	0.005	AVP
renal water absorption	1	802.5×	0.005	AVP
glycerol transmembrane transport	1	702.2×	0.005	AQP2
response to salt stress	1	624.1×	0.005	AVP
positive regulation of prostaglandin biosynthetic process	1	624.1×	0.005	AVP
metanephric collecting duct development	1	561.7×	0.005	AQP2
positive regulation of systemic arterial blood pressure	1	468.1×	0.006	AVP
multicellular organismal response to stress	1	432.1×	0.006	AVP
grooming behavior	1	374.5×	0.006	AVP
maternal behavior	1	374.5×	0.006	AVP
response to peptide	1	374.5×	0.006	AVP
vasoconstriction	1	295.6×	0.007	AVP
response to electrical stimulus	1	216.1×	0.009	AVP
cellular response to copper ion	1	208.1×	0.009	AQP2
positive regulation of vasoconstriction	1	200.6×	0.009	AVP
renal water homeostasis	1	170.2×	0.010	AQP2
response to testosterone	1	156.0×	0.011	AVP
response to nicotine	1	140.4×	0.011	AVP
symbiont entry into host cell	1	133.8×	0.012	AVP
generation of precursor metabolites and energy	1	114.6×	0.013	AVP

Therapeutics

Drugs indicated for this disease

1 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Vasopressin	Approved (phase 4)
Desmopressin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Atorvastatin.

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AQP2	0	0
MATN4	0	0
AVP	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
AQP2	5	ADMET:4, Binding: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

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	3	AQP2, MATN4, AVP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AQP2	5	—
MATN4	0	—
AVP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 16.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	13
PHASE2	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06368817	PHASE2	RECRUITING	A Study of Lower Radiotherapy Dose to Treat Children With CNS Germinoma
NCT06676774	PHASE2	RECRUITING	Effect of Intranasal Oxytocin on Emotion Recognition and Acute Psycho-Social Stress-induced Cortisol Increase in Patients With Central Diabetes Insipidus and Healthy Controls
NCT02460354	PHASE1	TERMINATED	Metformin and Congenital Nephrogenic Diabetes Insipidus
NCT02841553	Not specified	RECRUITING	Wolfram Syndrome and WFS1-related Disorders International Registry and Clinical Study
NCT07361263	Not specified	RECRUITING	Plasma Oxytocin Response to Oral Estrogens in Healthy Controls and AVP-Deficiency
NCT00004363	Not specified	COMPLETED	Study of the Pathogenesis and Pathophysiology of Familial Neurohypophyseal Diabetes Insipidus
NCT00004364	Not specified	UNKNOWN	Study of Novel Types of Familial Diabetes Insipidus
NCT00757276	Not specified	COMPLETED	Copeptin in the Diagnosis and Differential Diagnosis of Diabetes Insipidus. The CoSIP-Study
NCT01940614	Not specified	COMPLETED	Use of Copeptin in Diabetes Insipidus
NCT02132676	Not specified	COMPLETED	Shared Health Appointments and Reciprocal Enhanced Support
NCT02455414	Not specified	COMPLETED	Tracking Neurodegeneration in Early Wolfram Syndrome
NCT02523001	Not specified	COMPLETED	Effect of Statin Treatment on Urinary AQP2 (uAQP2/01)
NCT03572166	Not specified	COMPLETED	Use of Copeptin Measurement After Arginine Infusion for the Differential Diagnosis of Diabetes Insipidus - the CARGOx Study
NCT04351945	Not specified	UNKNOWN	Endocrine Changes and Their Correction in Heart and Lung Transplant Recipients and Donors
NCT04550520	Not specified	COMPLETED	Copeptin After a Subcutaneous Stimulation With Glucagon in Adults
NCT04648137	Not specified	COMPLETED	Circulating Oxytocin Changes in Response to the Oxytocin System Stimulator MDMA in Patients With Diabetes Insipidus and Healthy Controls

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DESMOPRESSIN	4	2
CARBOPLATIN	4	1
CHLORPROPAMIDE	4	1
ESTRADIOL VALERATE	4	1
GLUCAGON	4	1
CHEMBL4175452	0	1