Nephrogenic syndrome of inappropriate antidiuresis

Summary

Nephrogenic syndrome of inappropriate antidiuresis (MONDO:0010356) is a disease caused by AVPR2 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AVPR2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 63
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		21	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	nephrogenic syndrome of inappropriate antidiuresis
Mondo ID	MONDO:0010356
MeSH	C564491
OMIM	300539
Orphanet	93606
DOID	DOID:0112121
ICD-11	808905140
SNOMED CT	723440000
UMLS	C1845202
MedGen	336877
GARD	0010306
Is cancer (heuristic)	no

Also known as: nephrogenic syndrome of inappropriate antidiuresis · nephrogenic syndrome of inappropriate antidiuresis, X-linked recessive · NSIAD

Data availability: 63 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › renal tubule disorder › inherited renal tubular disease › nephrogenic syndrome of inappropriate antidiuresis

Related subtypes (27): cranioectodermal dysplasia, cystinuria, hereditary renal hypouricemia, nephrogenic diabetes insipidus-intracranial calcification syndrome, Gitelman syndrome, oculocerebrorenal syndrome, RHYNS syndrome, renal tubular acidosis, distal, 3, with or without sensorineural hearing loss, autosomal recessive proximal renal tubular acidosis, EAST syndrome, familial juvenile hyperuricemic nephropathy type 2, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, Bartter syndrome, Dent disease, nephrogenic diabetes insipidus, autosomal dominant proximal renal tubular acidosis, Senior-Loken syndrome, familial primary hypomagnesemia, mitochondrial DNA depletion syndrome, hepatocerebrorenal form, Jeune syndrome, nephronophthisis, pseudohypoaldosteronism type 1, Senior-Boichis syndrome, pseudohypoparathyroidism, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, HELIX syndrome, inherited Fanconi renotubular syndrome

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

63 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 9 conflicting classifications of pathogenicity, 8 benign/likely benign, 7 likely pathogenic, 6 pathogenic, 6 likely benign, 2 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
10844	NM_000054.7(AVPR2):c.1009C>T (p.Arg337Ter)	AVPR2	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
10854	NM_000054.7(AVPR2):c.409C>T (p.Arg137Cys)	AVPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
10855	NM_000054.7(AVPR2):c.410G>T (p.Arg137Leu)	AVPR2	Pathogenic	no assertion criteria provided
1203715	NM_000054.7(AVPR2):c.604C>T (p.Arg202Cys)	AVPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2577986	NM_000054.7(AVPR2):c.262G>A (p.Val88Met)	AVPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
3382215	NM_000054.7(AVPR2):c.135_136del (p.Ile46fs)	AVPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
585474	NM_000054.7(AVPR2):c.383A>C (p.Tyr128Ser)	AVPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10853	NM_000054.7(AVPR2):c.310C>T (p.Arg104Cys)	AVPR2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2584683	NM_000054.7(AVPR2):c.185T>C (p.Leu62Pro)	AVPR2	Likely pathogenic	criteria provided, single submitter
3356326	NM_000054.7(AVPR2):c.815dup (p.Met272fs)	AVPR2	Likely pathogenic	criteria provided, single submitter
35744	NM_000054.7(AVPR2):c.752_758del (p.Arg251fs)	AVPR2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3598165	NM_000054.7(AVPR2):c.206_210del (p.Gly69fs)	AVPR2	Likely pathogenic	criteria provided, single submitter
3598170	NM_000054.7(AVPR2):c.474del (p.Pro159fs)	AVPR2	Likely pathogenic	criteria provided, single submitter
3598175	NM_000054.7(AVPR2):c.685T>G (p.Phe229Val)	AVPR2	Likely pathogenic	criteria provided, single submitter
2219485	NM_000054.7(AVPR2):c.101C>T (p.Pro34Leu)	AVPR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2404671	NM_000054.7(AVPR2):c.193C>T (p.Arg65Trp)	AVPR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2577303	NM_000054.7(AVPR2):c.1018C>T (p.Leu340Phe)	AVPR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3132443	NM_000054.7(AVPR2):c.689G>A (p.Arg230Gln)	AVPR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3234058	NM_000054.7(AVPR2):c.575G>C (p.Cys192Ser)	AVPR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3598177	NM_000054.7(AVPR2):c.738G>C (p.Gly246=)	AVPR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3598187	NM_000054.7(AVPR2):c.1076C>T (p.Thr359Ile)	AVPR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
441086	NM_000054.7(AVPR2):c.797T>C (p.Val266Ala)	AVPR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
804118	NM_000054.7(AVPR2):c.191GGCGGGGCC[1] (p.64RRG[1])	AVPR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1219450	NM_000054.7(AVPR2):c.446G>A (p.Arg149His)	AVPR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2279588	NM_000054.7(AVPR2):c.730C>A (p.Pro244Thr)	AVPR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3598161	NM_000054.7(AVPR2):c.31C>G (p.Pro11Ala)	AVPR2	Uncertain significance	criteria provided, single submitter
3598162	NM_000054.7(AVPR2):c.46CTGCCCAGC[3] (p.Ser21_Asn22insLeuProSer)	AVPR2	Uncertain significance	criteria provided, single submitter
3598163	NM_000054.7(AVPR2):c.137T>C (p.Ile46Thr)	AVPR2	Uncertain significance	criteria provided, single submitter
3598164	NM_000054.7(AVPR2):c.200G>A (p.Arg67Gln)	AVPR2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
AVPR2	Definitive	X-linked	diabetes insipidus, nephrogenic, X-linked	8

Orphanet rare-disease linkage (cohort genes)

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

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
AVPR2	HGNC:897	ENSG00000126895	P30518	Vasopressin V2 receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AVPR2	Vasopressin V2 receptor	G-protein-coupled receptor for arginine vasopressin, an antidiuretic that promotes renal water reabsorption.

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
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AVPR2	GPCR	yes		Vprsn_rcpt_V2, GPCR_Rhodpsn, Vasoprsn_rcpt

Expression context

Cohort genes with no expression data: 0.

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
apex of heart	1
olfactory bulb	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AVPR2	146		yes	apex of heart, type B pancreatic cell, olfactory bulb

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AVPR2	1,734

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AVPR2	P30518	42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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 AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI)	1	5710.0×	0.001	AVPR2
Vasopressin-like receptors	1	1903.3×	0.002	AVPR2
Vasopressin regulates renal water homeostasis via Aquaporins	1	265.6×	0.008	AVPR2
Cargo recognition for clathrin-mediated endocytosis	1	104.8×	0.014	AVPR2
Clathrin-mediated endocytosis	1	85.2×	0.014	AVPR2
G alpha (s) signalling events	1	73.2×	0.014	AVPR2

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
renal water retention	1	16852.0×	0.001	AVPR2
regulation of systemic arterial blood pressure by vasopressin	1	3370.4×	0.002	AVPR2
renal water absorption	1	2407.4×	0.002	AVPR2
hemostasis	1	1685.2×	0.002	AVPR2
positive regulation of systemic arterial blood pressure	1	1404.3×	0.002	AVPR2
activation of adenylate cyclase activity	1	1123.5×	0.002	AVPR2
telencephalon development	1	991.3×	0.002	AVPR2
positive regulation of intracellular signal transduction	1	648.1×	0.003	AVPR2
positive regulation of vasoconstriction	1	601.9×	0.003	AVPR2
cellular response to hormone stimulus	1	383.0×	0.004	AVPR2
response to cytokine	1	374.5×	0.004	AVPR2
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	337.0×	0.004	AVPR2
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	113.1×	0.012	AVPR2
negative regulation of cell population proliferation	1	42.1×	0.029	AVPR2
positive regulation of gene expression	1	38.7×	0.029	AVPR2
G protein-coupled receptor signaling pathway	1	36.2×	0.029	AVPR2
positive regulation of cell population proliferation	1	33.6×	0.030	AVPR2

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
AVPR2	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AVPR2	51	4

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

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: 1; 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	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: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases