Diabetes insipidus, nephrogenic, autosomal

Summary

Diabetes insipidus, nephrogenic, autosomal (MONDO:0007451) is a disease caused by AQP2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: AQP2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 188

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diabetes insipidus, nephrogenic, autosomal
Mondo ID	MONDO:0007451
OMIM	125800
DOID	DOID:0081061
UMLS	C1563706
MedGen	289643
GARD	0015058
Is cancer (heuristic)	no

Also known as: diabetes insipidus, nephrogenic, 2 · diabetes insipidus, nephrogenic, autosomal

Data availability: 188 ClinVar variants · 3 GenCC gene-disease records.

Disease family

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

Related subtypes (1): 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

188 retrieved; paginated sample, class counts are floors:

95 uncertain significance, 28 benign, 19 likely pathogenic, 15 pathogenic/likely pathogenic, 12 conflicting classifications of pathogenicity, 7 pathogenic, 6 benign/likely benign, 6 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1319413	NM_000486.6(AQP2):c.298G>A (p.Gly100Arg)	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
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
17831	NM_000486.6(AQP2):c.369del (p.Asn123fs)	AQP2	Pathogenic	criteria provided, single submitter
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
17834	NM_000486.6(AQP2):c.203A>G (p.Asn68Ser)	AQP2	Pathogenic	no assertion criteria provided
17839	NM_000486.6(AQP2):c.543C>G (p.Cys181Trp)	AQP2	Pathogenic	no assertion criteria provided
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
446860	NM_000486.6(AQP2):c.211G>A (p.Val71Met)	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
974414	NM_000486.6(AQP2):c.797_*17del (p.Pro266fs)	AQP2	Pathogenic	criteria provided, single submitter
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
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
17840	NM_000486.6(AQP2):c.721del (p.Glu241fs)	AQP2	Likely pathogenic	criteria provided, single submitter
17841	NM_000486.6(AQP2):c.727del (p.Asp243fs)	AQP2	Likely pathogenic	criteria provided, single submitter
17845	NM_000486.6(AQP2):c.568G>A (p.Ala190Thr)	AQP2	Likely pathogenic	criteria provided, single submitter
3574907	NM_000486.6(AQP2):c.267C>A (p.Tyr89Ter)	AQP2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
AQP2	Strong	Autosomal dominant	diabetes insipidus, nephrogenic, autosomal	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AQP2	Orphanet:223	Arginine vasopressin resistance

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AQP2	HGNC:634	ENSG00000167580	P41181	Aquaporin-2	gencc,clinvar
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.
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: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AQP2	Other/Unknown	no		MIP, MIP_CS, Aquaporin-like
AQP5-AS1	Other/Unknown	no		MIAC

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephros cortex	1
renal medulla	1
seminal vesicle	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
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: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AQP2	3,471
AQP5-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AQP2	P41181	7

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: 4. Enrichment computed across 2 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
Passive transport by Aquaporins	1	878.5×	0.005	AQP2
Aquaporin-mediated transport	1	368.4×	0.005	AQP2
Vasopressin regulates renal water homeostasis via Aquaporins	1	265.6×	0.005	AQP2
Transport of small molecules	1	25.1×	0.040	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
actin filament organization	2	118.7×	8e-04	AQP2, AQP5-AS1
renal water transport	1	2808.7×	1e-03	AQP2
cellular response to water deprivation	1	2808.7×	1e-03	AQP2
cellular response to mercury ion	1	2808.7×	1e-03	AQP2
glycerol transmembrane transport	1	1053.2×	0.002	AQP2
regulation of epidermal growth factor receptor signaling pathway	1	842.6×	0.002	AQP5-AS1
metanephric collecting duct development	1	842.6×	0.002	AQP2
water transport	1	495.6×	0.003	AQP2
cellular response to copper ion	1	312.1×	0.004	AQP2
renal water homeostasis	1	255.3×	0.004	AQP2
protein homotetramerization	1	118.7×	0.008	AQP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
AQP5-AS1	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: 1; 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	2	AQP2, AQP5-AS1

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)
AQP2	5	—
AQP5-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.