Familial renal glucosuria

Summary

Familial renal glucosuria (MONDO:0009297) is a disease caused by SLC5A2 (GenCC Definitive), with 4 cohort genes and 2 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: SLC5A2 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 255
• Phenotypes (HPO): 13
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000112	Nephropathy	Obligate (100%)
HP:0000124	Renal tubular dysfunction	Obligate (100%)
HP:0003076	Glycosuria	Obligate (100%)
HP:0000010	Recurrent urinary tract infections	Occasional (5-29%)
HP:0001944	Dehydration	Occasional (5-29%)
HP:0001946	Ketosis	Occasional (5-29%)
HP:0008855	Moderate postnatal growth retardation	Occasional (5-29%)
HP:0000805	Enuresis	Excluded (0%)
HP:0000855	Insulin resistance	Excluded (0%)
HP:0003074	Hyperglycemia	Excluded (0%)
HP:0004924	Abnormal oral glucose tolerance	Excluded (0%)
HP:0040214	Abnormal circulating insulin concentration	Excluded (0%)
HP:0040217	Elevated hemoglobin A1c	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial renal glucosuria
Mondo ID	MONDO:0009297
MeSH	D006030
OMIM	233100
Orphanet	69076
DOID	DOID:0070613, DOID:9432
ICD-11	381783069
SNOMED CT	267430007
UMLS	C3245525
MedGen	757652
GARD	0007548
MedDRA	10038457
NORD	1658
Is cancer (heuristic)	no

Also known as: familial renal glucosuria · GLYS · renal glucosuria · Renal Glycosuria · renal glycosuria · SGLT2 deficiency

Data availability: 255 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › renal tubular transport disease › familial renal glucosuria

Related subtypes (8): Fanconi renotubular syndrome, renal tubular acidosis, Liddle syndrome, renal hypomagnesemia 3, Gitelman syndrome, Bartter syndrome, Dent disease, pseudohypoaldosteronism

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

255 retrieved; paginated sample, class counts are floors:

188 uncertain significance, 22 likely pathogenic, 20 conflicting classifications of pathogenicity, 13 pathogenic, 4 benign, 3 pathogenic/likely pathogenic, 3 likely benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12904	NM_003041.4(SLC5A2):c.1320G>A (p.Trp440Ter)	SLC5A2	Pathogenic	no assertion criteria provided
253135	NM_003041.4(SLC5A2):c.265G>A (p.Ala89Thr)	SLC5A2	Pathogenic	no assertion criteria provided
2577426	NM_003041.4(SLC5A2):c.469-2A>T	SLC5A2	Pathogenic	no assertion criteria provided
2577432	NM_003041.4(SLC5A2):c.1555_1576del (p.Ala519fs)	SLC5A2	Pathogenic/Likely pathogenic	no assertion criteria provided
2635987	NM_003041.4(SLC5A2):c.506del (p.Ala169fs)	SLC5A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29880	NM_003041.4(SLC5A2):c.127-16C>A	SLC5A2	Pathogenic	no assertion criteria provided
29881	NM_003041.4(SLC5A2):c.1435C>G (p.Arg479Gly)	SLC5A2	Pathogenic	no assertion criteria provided
29882	NM_003041.4(SLC5A2):c.294C>A (p.Phe98Leu)	SLC5A2	Pathogenic	no assertion criteria provided
3066386	NM_003041.4(SLC5A2):c.1499_1506del (p.Leu500fs)	SLC5A2	Pathogenic	criteria provided, single submitter
3256614	NM_003041.4(SLC5A2):c.1665+1del	SLC5A2	Pathogenic	criteria provided, single submitter
3580341	NM_003041.4(SLC5A2):c.1319G>A (p.Trp440Ter)	SLC5A2	Pathogenic	criteria provided, single submitter
4277263	NM_003041.4(SLC5A2):c.1281-1G>A	SLC5A2	Pathogenic	criteria provided, single submitter
4818944	NM_003041.4(SLC5A2):c.617dup (p.Val207fs)	SLC5A2	Pathogenic	criteria provided, single submitter
522538	NM_003041.4(SLC5A2):c.1291del (p.Val431fs)	SLC5A2	Pathogenic	no assertion criteria provided
804477	NM_003041.4(SLC5A2):c.294_295insTT (p.Glu99fs)	SLC5A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30150	NM_005359.6(SMAD4):c.1498A>G (p.Ile500Val)	SMAD4	Pathogenic	criteria provided, multiple submitters, no conflicts
3256905	NM_003041.4(SLC5A2):c.1830C>A (p.Cys610Ter)	RUSF1	Likely pathogenic	criteria provided, single submitter
4072224	NM_003041.4(SLC5A2):c.1792+1G>C	RUSF1	Likely pathogenic	criteria provided, single submitter
1285213	NM_003041.4(SLC5A2):c.1102C>T (p.Arg368Trp)	SLC5A2	Likely pathogenic	criteria provided, single submitter
1297591	NM_003041.4(SLC5A2):c.1280+1G>A	SLC5A2	Likely pathogenic	criteria provided, single submitter
2433567	NM_003041.4(SLC5A2):c.1153_1162del (p.Val385fs)	SLC5A2	Likely pathogenic	criteria provided, single submitter
3256638	NM_003041.4(SLC5A2):c.434T>G (p.Leu145Arg)	SLC5A2	Likely pathogenic	criteria provided, single submitter
3580284	NM_003041.4(SLC5A2):c.333G>A (p.Trp111Ter)	SLC5A2	Likely pathogenic	criteria provided, single submitter
3580288	NM_003041.4(SLC5A2):c.394C>T (p.Arg132Cys)	SLC5A2	Likely pathogenic	criteria provided, single submitter
3580289	NM_003041.4(SLC5A2):c.409C>T (p.Arg137Cys)	SLC5A2	Likely pathogenic	criteria provided, single submitter
3580320	NM_003041.4(SLC5A2):c.962A>G (p.Lys321Arg)	SLC5A2	Likely pathogenic	criteria provided, single submitter
3580326	NM_003041.4(SLC5A2):c.1066G>A (p.Gly356Ser)	SLC5A2	Likely pathogenic	criteria provided, single submitter
3580339	NM_003041.4(SLC5A2):c.1262_1280dup (p.Leu428fs)	SLC5A2	Likely pathogenic	criteria provided, single submitter
3580340	NM_003041.4(SLC5A2):c.1281-2A>G	SLC5A2	Likely pathogenic	criteria provided, single submitter
3580344	NM_003041.4(SLC5A2):c.1361del (p.Asp454fs)	SLC5A2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · 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
SLC5A2	Definitive	Autosomal recessive	familial renal glucosuria	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC5A2	Orphanet:69076	Familial renal glucosuria
SMAD4	Orphanet:1333	Familial pancreatic carcinoma
SMAD4	Orphanet:2588	Myhre syndrome
SMAD4	Orphanet:329971	Generalized juvenile polyposis/juvenile polyposis coli
SMAD4	Orphanet:774	Hereditary hemorrhagic telangiectasia
SMAD4	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

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
SLC5A2	HGNC:11037	ENSG00000140675	P31639	Sodium/glucose cotransporter 2	gencc,clinvar
SLITRK2	HGNC:13449	ENSG00000185985	Q9H156	SLIT and NTRK-like protein 2	clinvar
RUSF1	HGNC:25848	ENSG00000140688	Q96GQ5	RUS family member 1	clinvar
SMAD4	HGNC:6770	ENSG00000141646	Q13485	SMAD family member 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC5A2	Sodium/glucose cotransporter 2	Electrogenic Na(+)-coupled sugar symporter that actively transports D-glucose at the plasma membrane, with a Na(+) to sugar coupling ratio of 1:1.
SLITRK2	SLIT and NTRK-like protein 2	It is involved in synaptogenesis and promotes excitatory synapse differentiation.
SMAD4	SMAD family member 4	In muscle physiology, plays a central role in the balance between atrophy and hypertrophy.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC5A2	Other/Unknown	no		Na/solute_symporter, Na/solute_symporter_CS, Na/Glc_symporter_sf
SLITRK2	Other/Unknown	no		LRRNT, Cys-rich_flank_reg_C, Leu-rich_rpt
RUSF1	Other/Unknown	no		RUS_fam, UVB_sens_RUS_dom, UVB_sens_C
SMAD4	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf

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
ventricular zone	2
adult mammalian kidney	1
male germ line stem cell (sensu Vertebrata) in testis	1
nephron tubule	1
caudate nucleus	1
medial globus pallidus	1
adenohypophysis	1
left ovary	1
right ovary	1
calcaneal tendon	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC5A2	171	tissue_specific	marker	nephron tubule, adult mammalian kidney, male germ line stem cell (sensu Vertebrata) in testis
SLITRK2	166	broad	marker	ventricular zone, medial globus pallidus, caudate nucleus
RUSF1	260	ubiquitous	marker	adenohypophysis, left ovary, right ovary
SMAD4	288	ubiquitous	marker	ventricular zone, ganglionic eminence, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMAD4	7,320
SLC5A2	1,572
SLITRK2	1,442
RUSF1	765

Intra-cohort edges

A	B	Sources
RUSF1	SLC5A2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC5A2	P31639	12
SMAD4	Q13485	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RUSF1	Q96GQ5	85.65
SLITRK2	Q9H156	67.16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 58. 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
Defective SLC5A2 causes renal glucosuria (GLYS1)	1	3806.7×	0.011	SLC5A2
Loss of Function of SMAD4 in Cancer	1	1268.9×	0.011	SMAD4
SMAD4 MH2 Domain Mutants in Cancer	1	1268.9×	0.011	SMAD4
SMAD2/3 MH2 Domain Mutants in Cancer	1	1268.9×	0.011	SMAD4
RUNX3 regulates BCL2L11 (BIM) transcription	1	761.3×	0.013	SMAD4
Loss of Function of SMAD2/3 in Cancer	1	634.4×	0.013	SMAD4
Signaling by TGF-beta Receptor Complex in Cancer	1	634.4×	0.013	SMAD4
RUNX3 regulates CDKN1A transcription	1	543.8×	0.013	SMAD4
Transcriptional regulation of brown and beige adipocyte differentiation	1	380.7×	0.017	SMAD4
RUNX2 regulates bone development	1	271.9×	0.017	SMAD4
Signaling by Activin	1	253.8×	0.017	SMAD4
Formation of definitive endoderm	1	237.9×	0.017	SMAD4
FOXO-mediated transcription of cell cycle genes	1	223.9×	0.017	SMAD4
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	1	223.9×	0.017	SMAD4
Germ layer formation at gastrulation	1	223.9×	0.017	SMAD4
Receptor-type tyrosine-protein phosphatases	1	190.3×	0.018	SLITRK2
Cellular hexose transport	1	181.3×	0.018	SLC5A2
Transcriptional regulation of pluripotent stem cells	1	181.3×	0.018	SMAD4
Signaling by NODAL	1	165.5×	0.018	SMAD4
TGFBR3 expression	1	152.3×	0.018	SMAD4
Cardiogenesis	1	141.0×	0.018	SMAD4
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	126.9×	0.018	SMAD4
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	1	126.9×	0.018	SMAD4
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	122.8×	0.018	SMAD4
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	122.8×	0.018	SMAD4
Signaling by TGFBR3	1	122.8×	0.018	SMAD4
Signaling by BMP	1	119.0×	0.018	SMAD4
FOXO-mediated transcription	1	112.0×	0.018	SMAD4
TGF-beta receptor signaling activates SMADs	1	108.8×	0.018	SMAD4
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	102.9×	0.019	SMAD4

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
obsolete positive regulation of cell proliferation involved in heart valve morphogenesis	1	5617.3×	0.005	SMAD4
female gonad morphogenesis	1	5617.3×	0.005	SMAD4
negative regulation of cardiac myofibril assembly	1	5617.3×	0.005	SMAD4
alpha-glucoside transport	1	2808.7×	0.005	SLC5A2
nephrogenic mesenchyme morphogenesis	1	2808.7×	0.005	SMAD4
renal D-glucose absorption	1	1872.4×	0.005	SLC5A2
metanephric mesenchyme morphogenesis	1	1872.4×	0.005	SMAD4
atrioventricular valve formation	1	1404.3×	0.005	SMAD4
left ventricular cardiac muscle tissue morphogenesis	1	1404.3×	0.005	SMAD4
regulation of transforming growth factor beta2 production	1	1404.3×	0.005	SMAD4
formation of anatomical boundary	1	1404.3×	0.005	SMAD4
regulation of hair follicle development	1	1404.3×	0.005	SMAD4
positive regulation of luteinizing hormone secretion	1	1123.5×	0.006	SMAD4
positive regulation of follicle-stimulating hormone secretion	1	936.2×	0.006	SMAD4
endocardial cell differentiation	1	936.2×	0.006	SMAD4
D-glucose import across plasma membrane	1	936.2×	0.006	SLC5A2
brainstem development	1	702.2×	0.007	SMAD4
sebaceous gland development	1	702.2×	0.007	SMAD4
mesendoderm development	1	624.1×	0.007	SMAD4
response to transforming growth factor beta	1	624.1×	0.007	SMAD4
positive regulation of extracellular matrix assembly	1	624.1×	0.007	SMAD4
endothelial cell activation	1	561.7×	0.007	SMAD4
neural crest cell differentiation	1	510.7×	0.007	SMAD4
somite rostral/caudal axis specification	1	510.7×	0.007	SMAD4
atrioventricular canal development	1	510.7×	0.007	SMAD4
epithelial to mesenchymal transition involved in endocardial cushion formation	1	468.1×	0.007	SMAD4
hexose transmembrane transport	1	468.1×	0.007	SLC5A2
positive regulation of cardiac muscle cell apoptotic process	1	401.2×	0.008	SMAD4
secondary palate development	1	401.2×	0.008	SMAD4
negative regulation of cardiac muscle hypertrophy	1	374.5×	0.008	SMAD4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
SLC5A2	ERTUGLIFLOZIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC5A2	16	4
SLITRK2	0	0
RUSF1	0	0
SMAD4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ERTUGLIFLOZIN	4	SLC5A2
BEXAGLIFLOZIN	4	SLC5A2
IPRAGLIFLOZIN	4	SLC5A2
CANAGLIFLOZIN ANHYDROUS	4	SLC5A2
TOFOGLIFLOZIN	4	SLC5A2
EMPAGLIFLOZIN	4	SLC5A2
TOFOGLIFLOZIN ANHYDROUS	4	SLC5A2
SOTAGLIFLOZIN	4	SLC5A2
DAPAGLIFLOZIN	4	SLC5A2
ENAVOGLIFLOZIN	3	SLC5A2
HENAGLIFLOZIN	3	SLC5A2
LUSEOGLIFLOZIN	2	SLC5A2
REMOGLIFLOZIN ETABONATE	2	SLC5A2
YM-543 FREE ACID	2	SLC5A2
LICOGLIFLOZIN	2	SLC5A2
SERGLIFLOZIN ETABONATE	2	SLC5A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC5A2	160	Binding:157, Functional:2, ADMET:1
SMAD4	6	Binding:6

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SLC5A2	160

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

16 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)
ERTUGLIFLOZIN	4	SLC5A2
BEXAGLIFLOZIN	4	SLC5A2
IPRAGLIFLOZIN	4	SLC5A2
CANAGLIFLOZIN ANHYDROUS	4	SLC5A2
TOFOGLIFLOZIN	4	SLC5A2
EMPAGLIFLOZIN	4	SLC5A2
TOFOGLIFLOZIN ANHYDROUS	4	SLC5A2
SOTAGLIFLOZIN	4	SLC5A2
DAPAGLIFLOZIN	4	SLC5A2
ENAVOGLIFLOZIN	3	SLC5A2
HENAGLIFLOZIN	3	SLC5A2
LUSEOGLIFLOZIN	2	SLC5A2
REMOGLIFLOZIN ETABONATE	2	SLC5A2
YM-543 FREE ACID	2	SLC5A2
LICOGLIFLOZIN	2	SLC5A2
SERGLIFLOZIN ETABONATE	2	SLC5A2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SLC5A2
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	SLITRK2, RUSF1, SMAD4

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)
SLITRK2	0	—
RUSF1	0	—
SMAD4	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT03965000	Not specified	UNKNOWN	Human Solute Carrier Family 5 Member 2 (SLC5A2) Deficiency and the Glucagon-Incretin Axis