Nephrogenic diabetes insipidus

Summary

Nephrogenic diabetes insipidus (MONDO:0016383) is a disease with 4 cohort genes and 7 clinical trials. Top therapeutic interventions include amiloride, calcitonin, and indomethacin.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 101
• Phenotypes (HPO): 21
• Clinical trials: 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.15	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.44	Specific population	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0009806	Nephrogenic diabetes insipidus	Obligate (100%)
HP:0003158	Hyposthenuria	Very frequent (80-99%)
HP:0003228	Hypernatremia	Very frequent (80-99%)
HP:0004906	Hypernatremic dehydration	Very frequent (80-99%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0001959	Polydipsia	Frequent (30-79%)
HP:0002017	Nausea and vomiting	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002039	Anorexia	Frequent (30-79%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0011106	Hypovolemia	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0000009	Functional abnormality of the bladder	Occasional (5-29%)
HP:0000072	Hydroureter	Occasional (5-29%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001263	Global developmental delay	Very rare (<1-4%)
HP:0001561	Polyhydramnios	Very rare (<1-4%)
HP:0010677	Enuresis nocturna	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	nephrogenic diabetes insipidus
Mondo ID	MONDO:0016383
MeSH	D018500
Orphanet	223
DOID	DOID:12387
ICD-10-CM	N25.1
ICD-11	1417669099
NCIT	C84919
SNOMED CT	111395007
UMLS	C0162283
MedGen	57876
GARD	0007178
MedDRA	10029147
NORD	1497
Is cancer (heuristic)	no

Also known as: ADH resistant diabetes insipidus · diabetes insipidus nephrogenic · diabetes insipidus nephrogenic type 1 · diabetes insipidus nephrogenic X-linked

Data availability: 101 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

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

Related subtypes (3): secondary hyperparathyroidism of renal origin, hypophosphatemic nephrolithiasis/osteoporosis 1, hypophosphatemic nephrolithiasis/osteoporosis 2

Subtypes (2): diabetes insipidus, nephrogenic, autosomal, diabetes insipidus, nephrogenic, X-linked

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

101 retrieved; paginated sample, class counts are floors:

37 likely pathogenic, 18 pathogenic/likely pathogenic, 16 uncertain significance, 8 pathogenic, 8 likely benign, 7 conflicting classifications of pathogenicity, 4 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1374721	NM_000486.6(AQP2):c.106C>T (p.Gln36Ter)	AQP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454564	NM_000486.6(AQP2):c.127C>T (p.Gln43Ter)	AQP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455736	NM_000486.6(AQP2):c.253C>T (p.Arg85Ter)	AQP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1526141	NM_000486.6(AQP2):c.127_128del (p.Gln43fs)	AQP2	Pathogenic	criteria provided, multiple submitters, no conflicts
17828	NM_000486.6(AQP2):c.559C>T (p.Arg187Cys)	AQP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17830	NM_000486.6(AQP2):c.190G>A (p.Gly64Arg)	AQP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17832	NM_000486.6(AQP2):c.439G>A (p.Ala147Thr)	AQP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17833	NM_000486.6(AQP2):c.377C>T (p.Thr126Met)	AQP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17842	NM_000486.6(AQP2):c.170A>C (p.Gln57Pro)	AQP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17843	NM_000486.6(AQP2):c.299G>T (p.Gly100Val)	AQP2	Pathogenic	criteria provided, multiple submitters, no conflicts
17844	NM_000486.6(AQP2):c.785C>T (p.Pro262Leu)	AQP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1809696	NM_000486.6(AQP2):c.502G>A (p.Val168Met)	AQP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2160877	NM_000486.6(AQP2):c.707_720dup (p.Glu241delinsCysTer)	AQP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
285666	NM_000486.6(AQP2):c.763C>T (p.Gln255Ter)	AQP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446861	NM_000486.6(AQP2):c.277C>T (p.Gln93Ter)	AQP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446862	NM_000486.6(AQP2):c.97_119del (p.Asn33fs)	AQP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
988214	NM_000486.6(AQP2):c.375del (p.Thr126fs)	AQP2	Pathogenic	no assertion criteria provided
998050	NM_000486.6(AQP2):c.3G>T (p.Met1Ile)	AQP2	Pathogenic	criteria provided, single submitter
17837	NM_000486.6(AQP2):c.374C>T (p.Thr125Met)	AQP5-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10838	NM_000054.7(AVPR2):c.614A>G (p.Tyr205Cys)	AVPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10849	NM_000054.7(AVPR2):c.410G>A (p.Arg137His)	AVPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
2138782	NM_000054.7(AVPR2):c.965C>T (p.Pro322Leu)	AVPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
35741	NM_000054.7(AVPR2):c.472del (p.Arg158fs)	AVPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
35742	NM_000054.7(AVPR2):c.554del (p.Gly185fs)	AVPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
35747	NM_000054.7(AVPR2):c.838dup (p.Tyr280fs)	AVPR2	Pathogenic	criteria provided, single submitter
3896670	NM_000054.7(AVPR2):c.152_159del (p.Val51fs)	AVPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
1516570	NM_000486.6(AQP2):c.360+1G>A	AQP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
17829	NM_000486.6(AQP2):c.646T>C (p.Ser216Pro)	AQP2	Likely pathogenic	criteria provided, single submitter
17835	NM_000486.6(AQP2):c.523G>A (p.Gly175Arg)	AQP2	Likely pathogenic	criteria provided, single submitter
17836	NM_000486.6(AQP2):c.772G>A (p.Glu258Lys)	AQP2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · 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
AVPR2	Definitive	X-linked	diabetes insipidus, nephrogenic, X-linked	8
AQP2	Strong	Autosomal dominant	diabetes insipidus, nephrogenic, autosomal	4
SLC14A1	No Known Disease Relationship	Autosomal recessive	nephrogenic diabetes insipidus	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AQP2	Orphanet:223	Arginine vasopressin resistance
AVPR2	Orphanet:223	Arginine vasopressin resistance
AVPR2	Orphanet:93606	Nephrogenic syndrome of inappropriate antidiuresis

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AQP2	HGNC:634	ENSG00000167580	P41181	Aquaporin-2	gencc,clinvar
AVPR2	HGNC:897	ENSG00000126895	P30518	Vasopressin V2 receptor	gencc,clinvar
SLC14A1	HGNC:10918	ENSG00000141469	Q13336	Urea transporter 1	gencc
AQP5-AS1	HGNC:55474	ENSG00000257588	A0A7L8Y648	Micropeptide inhibiting actin cytoskeleton	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.
AVPR2	Vasopressin V2 receptor	G-protein-coupled receptor for arginine vasopressin, an antidiuretic that promotes renal water reabsorption.
SLC14A1	Urea transporter 1	Mediates the transport of urea driven by a concentration gradient across the cell membrane of erythrocytes.
AQP5-AS1	Micropeptide inhibiting actin cytoskeleton	Reduces filamentous actin fibers by interacting with aquaporin AQP2 which leads to inhibition of the expression of SEPTIN4 and integrin ITGB4.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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	19.4×	0.151
GPCR	1	6.0×	0.235
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AQP2	Other/Unknown	no		MIP, MIP_CS, Aquaporin-like
AVPR2	GPCR	yes		Vprsn_rcpt_V2, GPCR_Rhodpsn, Vasoprsn_rcpt
SLC14A1	Transporter	yes		Urea_transporter, Ammonium/urea_transptr
AQP5-AS1	Other/Unknown	no		MIAC

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)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephros cortex	1
renal medulla	1
seminal vesicle	1
apex of heart	1
olfactory bulb	1
type B pancreatic cell	1
mucosa of urinary bladder	1
tibia	1
trabecular bone tissue	1
bone marrow cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
olfactory segment of nasal 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
AVPR2	146		yes	apex of heart, type B pancreatic cell, olfactory bulb
SLC14A1	211	broad	marker	tibia, mucosa of urinary bladder, trabecular bone tissue
AQP5-AS1	107	tissue_specific	marker	olfactory segment of nasal mucosa, bone marrow cell, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AQP2	3,471
AVPR2	1,734
SLC14A1	976
AQP5-AS1	0

Intra-cohort edges

A	B	Sources
AQP2	AVPR2	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AVPR2	P30518	42
AQP2	P41181	7
SLC14A1	Q13336	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AQP5-AS1	A0A7L8Y648	63.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 4 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
Vasopressin regulates renal water homeostasis via Aquaporins	2	177.1×	4e-04	AQP2, AVPR2
Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI)	1	1903.3×	0.003	AVPR2
Vasopressin-like receptors	1	634.4×	0.005	AVPR2
Passive transport by Aquaporins	1	292.8×	0.008	AQP2
SLC-mediated transport of organic cations	1	253.8×	0.008	SLC14A1
Aquaporin-mediated transport	1	122.8×	0.014	AQP2
Cargo recognition for clathrin-mediated endocytosis	1	34.9×	0.041	AVPR2
Clathrin-mediated endocytosis	1	28.4×	0.043	AVPR2
G alpha (s) signalling events	1	24.4×	0.045	AVPR2
Transport of small molecules	1	8.4×	0.115	AQP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
renal water retention	1	4213.0×	0.005	AVPR2
renal water transport	1	1404.3×	0.005	AQP2
cellular response to water deprivation	1	1404.3×	0.005	AQP2
cellular response to mercury ion	1	1404.3×	0.005	AQP2
actin filament organization	2	59.3×	0.005	AQP2, AQP5-AS1
urea transport	1	1053.2×	0.005	SLC14A1
regulation of systemic arterial blood pressure by vasopressin	1	842.6×	0.005	AVPR2
urea transmembrane transport	1	842.6×	0.005	SLC14A1
renal water absorption	1	601.9×	0.006	AVPR2
glycerol transmembrane transport	1	526.6×	0.006	AQP2
hemostasis	1	421.3×	0.006	AVPR2
regulation of epidermal growth factor receptor signaling pathway	1	421.3×	0.006	AQP5-AS1
metanephric collecting duct development	1	421.3×	0.006	AQP2
positive regulation of systemic arterial blood pressure	1	351.1×	0.007	AVPR2
activation of adenylate cyclase activity	1	280.9×	0.008	AVPR2
water transport	1	247.8×	0.008	AQP2
telencephalon development	1	247.8×	0.008	AVPR2
positive regulation of intracellular signal transduction	1	162.0×	0.011	AVPR2
cellular response to copper ion	1	156.0×	0.011	AQP2
positive regulation of vasoconstriction	1	150.5×	0.011	AVPR2
renal water homeostasis	1	127.7×	0.012	AQP2
cellular response to hormone stimulus	1	95.8×	0.015	AVPR2
response to cytokine	1	93.6×	0.015	AVPR2
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	84.3×	0.016	AVPR2
protein homotetramerization	1	59.3×	0.021	AQP2
transmembrane transport	1	42.1×	0.029	SLC14A1
establishment of localization in cell	1	40.1×	0.029	SLC14A1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	28.3×	0.040	AVPR2
negative regulation of cell population proliferation	1	10.5×	0.101	AVPR2
positive regulation of gene expression	1	9.7×	0.106	AVPR2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
AVPR2	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AVPR2	51	4
AQP2	0	0
SLC14A1	0	0
AQP5-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	AVPR2
AMOXAPINE	4	AVPR2
THIOTHIXENE	4	AVPR2
CINACALCET	4	AVPR2
PYRVINIUM	4	AVPR2
BALSALAZIDE	4	AVPR2
IPRINDOLE	4	AVPR2
SERTINDOLE	4	AVPR2
NITAZOXANIDE	4	AVPR2
PIMOZIDE	4	AVPR2
DESMOPRESSIN	4	AVPR2
RIFAXIMIN	4	AVPR2
TERFENADINE	4	AVPR2
CONIVAPTAN	4	AVPR2
NERATINIB	4	AVPR2
IDEBENONE	4	AVPR2
BOSUTINIB	4	AVPR2
LASOFOXIFENE	4	AVPR2
CARBETOCIN	4	AVPR2
TOLVAPTAN	4	AVPR2
VASOPRESSIN	4	AVPR2
RIFAMPIN	4	AVPR2
ATOSIBAN	4	AVPR2
OXYTOCIN	4	AVPR2
MEFLOQUINE	4	AVPR2
MOZAVAPTAN	4	AVPR2
TRIFLUOPERAZINE	4	AVPR2
NEBIVOLOL	4	AVPR2
FLUSPIRILENE	4	AVPR2
SUNITINIB	4	AVPR2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
AVPR2	309	Binding:208, Functional:100, ADMET:1
AQP2	5	ADMET:4, Binding:1
SLC14A1	3	Binding:3

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
AVPR2	309

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

30 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)
CLOTRIMAZOLE	4	AVPR2
AMOXAPINE	4	AVPR2
THIOTHIXENE	4	AVPR2
CINACALCET	4	AVPR2
PYRVINIUM	4	AVPR2
BALSALAZIDE	4	AVPR2
IPRINDOLE	4	AVPR2
SERTINDOLE	4	AVPR2
NITAZOXANIDE	4	AVPR2
PIMOZIDE	4	AVPR2
DESMOPRESSIN	4	AVPR2
RIFAXIMIN	4	AVPR2
TERFENADINE	4	AVPR2
CONIVAPTAN	4	AVPR2
NERATINIB	4	AVPR2
IDEBENONE	4	AVPR2
BOSUTINIB	4	AVPR2
LASOFOXIFENE	4	AVPR2
CARBETOCIN	4	AVPR2
TOLVAPTAN	4	AVPR2
VASOPRESSIN	4	AVPR2
RIFAMPIN	4	AVPR2
ATOSIBAN	4	AVPR2
OXYTOCIN	4	AVPR2
MEFLOQUINE	4	AVPR2
MOZAVAPTAN	4	AVPR2
TRIFLUOPERAZINE	4	AVPR2
NEBIVOLOL	4	AVPR2
FLUSPIRILENE	4	AVPR2
SUNITINIB	4	AVPR2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	AVPR2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	SLC14A1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	AQP2, AQP5-AS1

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	AVPR2
SLC14A1	3	—
AQP5-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05190744	PHASE2	COMPLETED	Probenecid (PB) to Treat Hereditary Nephrogenic Diabetes Insipidus (NDI), ADPKD Treated With Tolvaptan, and Severely Polyuric Patients With Previous Lithium Administration
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT06604975	Not specified	NOT_YET_RECRUITING	Arginin-stimulated Copeptin in Polyuria-polydipsia Syndrome in Children
NCT00478335	Not specified	COMPLETED	Pharmacologic Treatment of Congenital Nephrogenic Diabetes Insipidus
NCT04939753	Not specified	COMPLETED	Nephrogenic Diabetes Insipidus During Prolonged Sevoflurane Sedation in the ICU: a Retrospective Analysis
NCT05307042	Not specified	UNKNOWN	Decline in Renal Concentration Ability in Lithium Treated Patients
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AMILORIDE	4	1
CALCITONIN	4	1
INDOMETHACIN	4	1
SILDENAFIL	4	1