Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young

Summary

Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young (MONDO:0014458) is a disease caused by HNF4A (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: HNF4A (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 100

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young
Mondo ID	MONDO:0014458
OMIM	616026
DOID	DOID:0080760
UMLS	C4014962
MedGen	863399
GARD	0016048
Is cancer (heuristic)	no

Also known as: Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young · fanconi renotubular syndrome 4, with maturity-onset diabetes of the young · Fanconi syndrome caused by mutation in HNF4A · FRTS4 · HNF4A Fanconi syndrome

Data availability: 100 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › pancreas disorder › endocrine pancreas disorder › diabetes mellitus › monogenic diabetes › maturity-onset diabetes of the young › Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young

Related subtypes (14): maturity-onset diabetes of the young type 1, maturity-onset diabetes of the young type 2, renal cysts and diabetes syndrome, maturity-onset diabetes of the young type 3, maturity-onset diabetes of the young type 4, maturity-onset diabetes of the young type 6, maturity-onset diabetes of the young type 8, maturity-onset diabetes of the young type 7, maturity-onset diabetes of the young type 9, maturity-onset diabetes of the young type 10, maturity-onset diabetes of the young type 11, maturity-onset diabetes of the young type 13, maturity-onset diabetes of the young type 14, maturity-onset diabetes of the young, type 12

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

100 retrieved; paginated sample, class counts are floors:

54 uncertain significance, 13 conflicting classifications of pathogenicity, 8 benign/likely benign, 7 likely pathogenic, 7 pathogenic, 6 likely benign, 3 benign, 2 uncertain significance/uncertain risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
156152	NM_175914.5(HNF4A):c.187C>T (p.Arg63Trp)	HNF4A	Pathogenic	reviewed by expert panel
3238969	NM_175914.5(HNF4A):c.583-1G>A	HNF4A	Pathogenic	reviewed by expert panel
427034	NM_175914.5(HNF4A):c.335G>A (p.Arg112Gln)	HNF4A	Pathogenic	reviewed by expert panel
435436	NM_175914.5(HNF4A):c.200G>A (p.Arg67Gln)	HNF4A	Pathogenic	reviewed by expert panel
435439	NM_175914.5(HNF4A):c.944TGC[6] (p.Leu319dup)	HNF4A	Pathogenic	reviewed by expert panel
4818860	NM_175914.5(HNF4A):c.792T>A (p.Tyr264Ter)	HNF4A	Pathogenic	criteria provided, single submitter
994902	NM_175914.5(HNF4A):c.322G>A (p.Val108Ile)	HNF4A	Pathogenic	reviewed by expert panel
1186689	NM_175914.5(HNF4A):c.691C>T (p.Arg231Trp)	HNF4A	Likely pathogenic	reviewed by expert panel
3068533	NM_175914.5(HNF4A):c.124G>A (p.Gly42Arg)	HNF4A	Likely pathogenic	reviewed by expert panel
3587264	NM_175914.5(HNF4A):c.1217-1G>A	HNF4A	Likely pathogenic	criteria provided, single submitter
4526861	NM_175914.5(HNF4A):c.255C>A (p.Asp85Glu)	HNF4A	Likely pathogenic	criteria provided, single submitter
587398	NM_175914.5(HNF4A):c.427-1G>A	HNF4A	Likely pathogenic	reviewed by expert panel
689636	NM_175914.5(HNF4A):c.2T>C (p.Met1Thr)	HNF4A	Likely pathogenic	reviewed by expert panel
9212	NM_175914.5(HNF4A):c.340C>T (p.Arg114Trp)	HNF4A	Likely pathogenic	reviewed by expert panel
804915	NM_175914.5(HNF4A):c.358T>C (p.Ser120Pro)	HNF4A	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
899287	NM_175914.5(HNF4A):c.562G>A (p.Glu188Lys)	HNF4A	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
1098751	NM_175914.5(HNF4A):c.353G>A (p.Arg118Gln)	HNF4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1324537	NM_175914.5(HNF4A):c.1198C>T (p.Arg400Ter)	HNF4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1407239	NM_175914.5(HNF4A):c.841A>G (p.Ser281Gly)	HNF4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1442643	NM_175914.5(HNF4A):c.-79C>T	HNF4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1588338	NM_175914.5(HNF4A):c.657C>T (p.Asp219=)	HNF4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2920813	NM_175914.5(HNF4A):c.609C>T (p.Gly203=)	HNF4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3075823	NM_175914.5(HNF4A):c.1063+120G>A	HNF4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338432	NM_175914.5(HNF4A):c.*145T>A	HNF4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3587243	NM_175914.5(HNF4A):c.199C>A (p.Arg67=)	HNF4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3587256	NM_175914.5(HNF4A):c.702G>A (p.Pro234=)	HNF4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
447516	NM_175914.5(HNF4A):c.427-20C>T	HNF4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
449418	NM_175914.5(HNF4A):c.464G>A (p.Arg155Gln)	HNF4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
633668	NM_175914.5(HNF4A):c.791A>G (p.Tyr264Cys)	HNF4A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1172869	NM_175914.5(HNF4A):c.587C>A (p.Ala196Asp)	HNF4A	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
HNF4A	Definitive	Autosomal dominant	maturity-onset diabetes of the young type 1	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HNF4A	Orphanet:263455	Congenital hyperinsulinism due to HNF4A deficiency
HNF4A	Orphanet:544628	Atypical Fanconi syndrome-neonatal hyperinsulinism syndrome
HNF4A	Orphanet:552	MODY
SCNN1B	Orphanet:171876	Generalized pseudohypoaldosteronism type 1
SCNN1B	Orphanet:526	Liddle syndrome
SCNN1B	Orphanet:60033	Idiopathic bronchiectasis

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
HNF4A	HGNC:5024	ENSG00000101076	P41235	Hepatocyte nuclear factor 4-alpha	gencc,clinvar
SCNN1B	HGNC:10600	ENSG00000168447	P51168	Epithelial sodium channel subunit beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HNF4A	Hepatocyte nuclear factor 4-alpha	Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes.
SCNN1B	Epithelial sodium channel subunit beta	This is one of the three pore-forming subunits of the heterotrimeric epithelial sodium channel (ENaC), a critical regulator of sodium balance and fluid homeostasis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Nuclear receptor	1	192.9×	0.010
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HNF4A	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
SCNN1B	Other/Unknown	no		ENaC, ENaC_chordates, ENaC_CS

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
duodenum	1
mucosa of transverse colon	1
right lobe of liver	1
esophagus mucosa	1
lower esophagus mucosa	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HNF4A	110	tissue_specific	marker	right lobe of liver, mucosa of transverse colon, duodenum
SCNN1B	188	broad	marker	lower esophagus mucosa, esophagus mucosa, rectum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNF4A	4,731
SCNN1B	1,013

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HNF4A	P41235	8
SCNN1B	P51168	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sensory perception of salty taste	1	951.7×	0.009	SCNN1B
Nephron development	1	439.2×	0.010	HNF4A
Regulation of gene expression in beta cells	1	259.6×	0.012	HNF4A
Sensory perception of taste	1	167.9×	0.013	SCNN1B
Nuclear Receptor transcription pathway	1	100.2×	0.018	HNF4A
Stimuli-sensing channels	1	68.0×	0.022	SCNN1B
Ion channel transport	1	48.0×	0.024	SCNN1B
Sensory Perception	1	47.6×	0.024	SCNN1B
Transport of small molecules	1	12.6×	0.078	SCNN1B

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
regulation of growth hormone receptor signaling pathway	1	8426.0×	0.003	HNF4A
obsolete regulation of ornithine metabolic process	1	8426.0×	0.003	HNF4A
aldosterone metabolic process	1	4213.0×	0.004	SCNN1B
leukocyte activation involved in inflammatory response	1	2808.7×	0.004	SCNN1B
sensory perception of salty taste	1	2106.5×	0.004	SCNN1B
neutrophil-mediated killing of bacterium	1	2106.5×	0.004	SCNN1B
regulation of gastrulation	1	1404.3×	0.004	HNF4A
cellular response to aldosterone	1	1203.7×	0.004	SCNN1B
epithelial fluid transport	1	1053.2×	0.004	SCNN1B
cellular response to vasopressin	1	1053.2×	0.004	SCNN1B
neutrophil activation involved in immune response	1	936.2×	0.004	SCNN1B
artery smooth muscle contraction	1	936.2×	0.004	SCNN1B
multicellular organismal-level water homeostasis	1	842.6×	0.004	SCNN1B
sensory perception of sour taste	1	842.6×	0.004	SCNN1B
erythrocyte homeostasis	1	648.1×	0.005	SCNN1B
mucus secretion	1	648.1×	0.005	SCNN1B
renal system process	1	561.7×	0.005	SCNN1B
phospholipid homeostasis	1	495.6×	0.006	HNF4A
sodium ion homeostasis	1	468.1×	0.006	SCNN1B
sex differentiation	1	421.3×	0.006	HNF4A
intracellular sodium ion homeostasis	1	383.0×	0.006	SCNN1B
potassium ion homeostasis	1	383.0×	0.006	SCNN1B
cellular response to acidic pH	1	366.4×	0.006	SCNN1B
signal transduction involved in regulation of gene expression	1	351.1×	0.006	HNF4A
sodium ion import across plasma membrane	1	312.1×	0.007	SCNN1B
response to food	1	247.8×	0.008	SCNN1B
triglyceride homeostasis	1	240.7×	0.008	HNF4A
regulation of lipid metabolic process	1	216.1×	0.009	HNF4A
regulation of insulin secretion	1	195.9×	0.009	HNF4A
lung alveolus development	1	175.5×	0.010	SCNN1B

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HNF4A	0	0
SCNN1B	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
HNF4A	106	Binding:97, Functional:9
SCNN1B	5	Binding:3, ADMET:1, Functional:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
HNF4A	106

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	HNF4A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SCNN1B

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)
HNF4A	106	—
SCNN1B	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.