Inherited renal tubular disease

Summary

Inherited renal tubular disease (MONDO:0015962) is a disease (an umbrella term covering 28 Mondo subtypes) caused by variants in KCNJ16 and RRAGD, with 4 cohort genes.

At a glance

• Causal genes: KCNJ16 (GenCC Strong), RRAGD (GenCC Strong)
• Umbrella term: 28 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	inherited renal tubular disease
Mondo ID	MONDO:0015962
Orphanet	183592
UMLS	C5680544
MedGen	1826140
GARD	0020306
Anatomy (UBERON)	UBERON:0009773
Is cancer (heuristic)	no

Data availability: 1 ClinVar variant · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 28 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › renal tubule disorder › inherited renal tubular disease

Related subtypes (3): Fanconi renotubular syndrome, renal tubular acidosis, mucinous tubular and spindle renal cell carcinoma

Subtypes (28): cranioectodermal dysplasia, cystinuria, hereditary renal hypouricemia, nephrogenic diabetes insipidus-intracranial calcification syndrome, Gitelman syndrome, nephrogenic syndrome of inappropriate antidiuresis, 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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208612	NM_001126108.2(SLC12A3):c.2221G>A (p.Gly741Arg)	SLC12A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
KCNJ16	Strong	Autosomal recessive	inherited renal tubular disease	3
RRAGD	Strong	Autosomal dominant	hypomagnesemia 7, renal, with or without dilated cardiomyopathy	3
EHD1	Moderate	Autosomal recessive	inherited renal tubular disease

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RRAGD	Orphanet:73224	Kidney tubulopathy-dilated cardiomyopathy syndrome
SLC12A3	Orphanet:358	Gitelman syndrome

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
RRAGD	HGNC:19903	ENSG00000025039	Q9NQL2	Ras-related GTP-binding protein D	gencc
EHD1	HGNC:3242	ENSG00000110047	Q9H4M9	EH domain-containing protein 1	gencc
KCNJ16	HGNC:6262	ENSG00000153822	Q9NPI9	Inward rectifier potassium channel 16	gencc
SLC12A3	HGNC:10912	ENSG00000070915	P55017	Solute carrier family 12 member 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RRAGD	Ras-related GTP-binding protein D	Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade.
EHD1	EH domain-containing protein 1	ATP- and membrane-binding protein that controls membrane reorganization/tubulation upon ATP hydrolysis.
KCNJ16	Inward rectifier potassium channel 16	Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.
SLC12A3	Solute carrier family 12 member 3	Electroneutral sodium and chloride ion cotransporter, which acts as a key mediator of sodium and chloride reabsorption in kidney distal convoluted tubules.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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	27.9×	0.071
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RRAGD	Other/Unknown	no		Gtr1_RagA, P-loop_NTPase, RagC/D
EHD1	Other/Unknown	no		EH_dom, EF_hand_dom, EF-hand-dom_pair
KCNJ16	Ion channel	yes		K_chnl_inward-rec_Kir5, K_chnl_inward-rec_Kir_cyto, Ig_E-set
SLC12A3	Other/Unknown	no		SLC12A3, AA-permease/SLC12A_dom, SLC12A_fam

Expression context

Cohort genes with no expression data: 0.

4 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
nephron tubule	2
body of tongue	1
parotid gland	1
skeletal muscle tissue of rectus abdominis	1
granulocyte	1
left testis	1
right testis	1
caput epididymis	1
renal medulla	1
adult mammalian kidney	1
kidney	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RRAGD	290	ubiquitous	marker	body of tongue, parotid gland, skeletal muscle tissue of rectus abdominis
EHD1	284	ubiquitous	marker	left testis, right testis, granulocyte
KCNJ16	212	broad	marker	renal medulla, nephron tubule, caput epididymis
SLC12A3	85	tissue_specific	marker	adult mammalian kidney, nephron tubule, kidney

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EHD1	1,617
SLC12A3	1,365
RRAGD	1,187
KCNJ16	894

Intra-cohort edges

A	B	Sources
KCNJ16	SLC12A3	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC12A3	P55017	12
EHD1	Q9H4M9	5
KCNJ16	Q9NPI9	4
RRAGD	Q9NQL2	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 40. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC12A3 causes Gitelman syndrome (GS)	1	2855.0×	0.014	SLC12A3
Potassium transport channels	1	951.7×	0.021	KCNJ16
Cation-coupled Chloride cotransporters	1	407.9×	0.033	SLC12A3
G protein gated Potassium channels	1	285.5×	0.035	KCNJ16
Inwardly rectifying K+ channels	1	178.4×	0.037	KCNJ16
Activation of GABAB receptors	1	150.3×	0.037	KCNJ16
GABA B receptor activation	1	135.9×	0.037	KCNJ16
mTORC1-mediated signalling	1	119.0×	0.037	RRAGD
Activation of G protein gated Potassium channels	1	98.5×	0.037	KCNJ16
Energy dependent regulation of mTOR by LKB1-AMPK	1	98.5×	0.037	RRAGD
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	98.5×	0.037	KCNJ16
GABA receptor activation	1	79.3×	0.042	KCNJ16
MTOR signalling	1	66.4×	0.046	RRAGD
PTEN Regulation	1	57.1×	0.050	RRAGD
SLC transporter disorders	1	51.0×	0.050	SLC12A3
Amino acids regulate mTORC1	1	50.1×	0.050	RRAGD
Regulation of PTEN gene transcription	1	44.6×	0.052	RRAGD
Cellular response to starvation	1	41.4×	0.053	RRAGD
Autophagy	1	37.1×	0.053	RRAGD
Disorders of transmembrane transporters	1	34.8×	0.053	SLC12A3
Potassium Channels	1	33.6×	0.053	KCNJ16
R-HSA-425393	1	32.4×	0.053	SLC12A3
TP53 Regulates Metabolic Genes	1	32.4×	0.053	RRAGD
Macroautophagy	1	28.8×	0.057	RRAGD
Neurotransmitter receptors and postsynaptic signal transmission	1	25.0×	0.063	KCNJ16
Intracellular signaling by second messengers	1	22.8×	0.066	RRAGD
Transmission across Chemical Synapses	1	19.0×	0.076	KCNJ16
PIP3 activates AKT signaling	1	16.7×	0.081	RRAGD
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.081	EHD1
Transcriptional Regulation by TP53	1	15.5×	0.084	RRAGD

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
potassium ion import across plasma membrane	2	183.2×	0.002	SLC12A3, KCNJ16
positive regulation of endocytic recycling	1	702.2×	0.014	EHD1
positive regulation of cholesterol storage	1	601.9×	0.014	EHD1
response to salt	1	526.6×	0.014	SLC12A3
response to aldosterone	1	421.3×	0.014	SLC12A3
chloride ion homeostasis	1	383.0×	0.014	SLC12A3
cellular response to L-leucine	1	351.1×	0.014	RRAGD
cellular response to leucine starvation	1	351.1×	0.014	RRAGD
positive regulation of myoblast fusion	1	263.3×	0.014	EHD1
low-density lipoprotein particle clearance	1	247.8×	0.014	EHD1
renal sodium ion absorption	1	247.8×	0.014	SLC12A3
sodium ion homeostasis	1	234.1×	0.014	SLC12A3
potassium ion homeostasis	1	191.5×	0.015	SLC12A3
regulation of monoatomic ion transmembrane transport	1	183.2×	0.015	KCNJ16
cell volume homeostasis	1	150.5×	0.017	SLC12A3
positive regulation of TOR signaling	1	123.9×	0.019	RRAGD
cellular response to nerve growth factor stimulus	1	117.0×	0.019	EHD1
protein localization to cilium	1	100.3×	0.021	EHD1
cellular response to amino acid stimulus	1	76.6×	0.025	RRAGD
positive regulation of TORC1 signaling	1	73.9×	0.025	RRAGD
sodium ion transport	1	68.0×	0.025	SLC12A3
endocytic recycling	1	66.9×	0.025	EHD1
negative regulation of autophagy	1	64.8×	0.025	RRAGD
chloride transmembrane transport	1	59.3×	0.027	SLC12A3
sodium ion transmembrane transport	1	50.8×	0.029	SLC12A3
cellular response to starvation	1	48.4×	0.029	RRAGD
potassium ion transport	1	47.9×	0.029	KCNJ16
monoatomic ion transport	1	39.0×	0.033	SLC12A3
cholesterol homeostasis	1	39.0×	0.033	EHD1
positive regulation of neuron projection development	1	34.2×	0.036	EHD1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
RRAGD	0	0
EHD1	0	0
KCNJ16	0	0
SLC12A3	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
EHD1	5	Binding:5
SLC12A3	1	Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	KCNJ16
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	RRAGD, EHD1, SLC12A3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RRAGD	0	—
EHD1	5	—
KCNJ16	0	—
SLC12A3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.