Hyperuricemic nephropathy, familial juvenile type 4

Summary

Hyperuricemic nephropathy, familial juvenile type 4 (MONDO:0014891) is a disease caused by SEC61A1 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: SEC61A1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperuricemic nephropathy, familial juvenile type 4
Mondo ID	MONDO:0014891
OMIM	617056
DOID	DOID:0061120
UMLS	C4310741
MedGen	934708
Is cancer (heuristic)	no

Also known as: ADTKD-SEC61A1 · familial juvenile hyperuricemic nephropathy caused by mutation in SEC61A1 · HNFJ4 · hyperuricemic nephropathy, familial juvenile, 4 · hyperuricemic nephropathy, familial juvenile, type 4 · SEC61A1 familial juvenile hyperuricemic nephropathy · SEC61A1-related autosomal dominant tubulointerstitial kidney disease · tubulointerstitial kidney disease, autosomal dominant, 5

Data availability: 15 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inherited kidney disorder › familial juvenile hyperuricemic nephropathy › hyperuricemic nephropathy, familial juvenile type 4

Related subtypes (5): familial juvenile hyperuricemic nephropathy type 1, familial juvenile hyperuricemic nephropathy type 2, hyperuricemic nephropathy, familial juvenile type 3, tubulointerstitial kidney disease, autosomal dominant, 2, tubulointerstitial kidney disease, autosomal dominant 6

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

15 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 3 pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1686175	NM_013336.4(SEC61A1):c.186C>A (p.Phe62Leu)	SEC61A1	Pathogenic	criteria provided, single submitter
253146	NM_013336.4(SEC61A1):c.553A>G (p.Thr185Ala)	SEC61A1	Pathogenic	no assertion criteria provided
253147	NM_013336.4(SEC61A1):c.200T>G (p.Val67Gly)	SEC61A1	Pathogenic	no assertion criteria provided
1804890	NM_013336.4(SEC61A1):c.265C>T (p.Leu89Phe)	SEC61A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
289815	NM_022436.3(ABCG5):c.293C>G (p.Ala98Gly)	ABCG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1341817	NM_013336.4(SEC61A1):c.616+7G>A	SEC61A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3159380	NM_013336.4(SEC61A1):c.1060G>A (p.Val354Met)	RUVBL1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3236200	NM_013336.4(SEC61A1):c.806C>T (p.Ser269Leu)	RUVBL1	Uncertain significance	criteria provided, single submitter
3588360	NM_013336.4(SEC61A1):c.1075G>A (p.Val359Ile)	RUVBL1	Uncertain significance	criteria provided, single submitter
4076399	NM_013336.4(SEC61A1):c.1220C>T (p.Thr407Ile)	RUVBL1	Uncertain significance	criteria provided, single submitter
4540434	NM_013336.4(SEC61A1):c.847C>T (p.Leu283Phe)	RUVBL1	Uncertain significance	criteria provided, single submitter
2435800	NM_013336.4(SEC61A1):c.299T>C (p.Ile100Thr)	SEC61A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3377057	NM_013336.4(SEC61A1):c.546C>A (p.Phe182Leu)	SEC61A1	Uncertain significance	criteria provided, single submitter
3381990	NM_013336.4(SEC61A1):c.376G>A (p.Gly126Ser)	SEC61A1	Uncertain significance	criteria provided, single submitter
1170774	NM_013336.4(SEC61A1):c.784C>A (p.Arg262=)	RUVBL1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · 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
SEC61A1	Strong	Autosomal dominant	hyperuricemic nephropathy, familial juvenile type 4	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SEC61A1	Orphanet:697417	Common variable immunodeficiency phenotype due to SEC61A1 deficiency
ABCG5	Orphanet:2882	Sitosterolemia
ABCG5	Orphanet:391665	Homozygous familial hypercholesterolemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SEC61A1	HGNC:18276	ENSG00000058262	P61619	Protein transport protein Sec61 subunit alpha isoform 1	gencc,clinvar
RUVBL1	HGNC:10474	ENSG00000175792	Q9Y265	RuvB-like 1	clinvar
ABCG5	HGNC:13886	ENSG00000138075	Q9H222	ATP-binding cassette sub-family G member 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SEC61A1	Protein transport protein Sec61 subunit alpha isoform 1	Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER).
RUVBL1	RuvB-like 1	Possesses single-stranded DNA-stimulated ATPase and ATP-dependent DNA helicase (3’ to 5’) activity; hexamerization is thought to be critical for ATP hydrolysis and adjacent subunits in the ring-like structure contribute to the ATPase activ…
ABCG5	ATP-binding cassette sub-family G member 5	ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Transporter	1	25.9×	0.076
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SEC61A1	Other/Unknown	no		SecY/SEC61-alpha, Translocon_Sec61/SecY_plug_dom, SecY_dom_sf
RUVBL1	Other/Unknown	no		AAA+_ATPase, TIP49_P-loop, RuvB-like
ABCG5	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
islet of Langerhans	1
stromal cell of endometrium	1
primordial germ cell in gonad	1
right uterine tube	1
ventricular zone	1
duodenum	1
jejunal mucosa	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SEC61A1	284	ubiquitous	marker	body of pancreas, stromal cell of endometrium, islet of Langerhans
RUVBL1	134	ubiquitous	marker	right uterine tube, ventricular zone, primordial germ cell in gonad
ABCG5	61	tissue_specific	marker	jejunal mucosa, right lobe of liver, duodenum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ABCG5	1,996
RUVBL1	1,549
SEC61A1	490

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RUVBL1	Q9Y265	36
SEC61A1	P61619	15
ABCG5	Q9H222	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 41. Enrichment computed across 3 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 ABCG8 causes GBD4 and sitosterolemia	1	1903.3×	0.011	ABCG5
Defective ABCG5 causes sitosterolemia	1	1903.3×	0.011	ABCG5
ABC transporters in lipid homeostasis	1	200.3×	0.031	ABCG5
Extension of Telomeres	1	200.3×	0.031	RUVBL1
Nucleosome assembly	1	158.6×	0.031	RUVBL1
Telomere Extension By Telomerase	1	152.3×	0.031	RUVBL1
Global Genome Nucleotide Excision Repair (GG-NER)	1	152.3×	0.031	RUVBL1
ABC transporter disorders	1	146.4×	0.031	ABCG5
NR1H2 and NR1H3-mediated signaling	1	131.3×	0.031	ABCG5
Telomere Maintenance	1	122.8×	0.031	RUVBL1
Antigen processing-Cross presentation	1	105.7×	0.031	SEC61A1
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	102.9×	0.031	ABCG5
DNA Damage Recognition in GG-NER	1	95.2×	0.031	RUVBL1
Nucleotide Excision Repair	1	95.2×	0.031	RUVBL1
Chromosome Maintenance	1	70.5×	0.039	RUVBL1
Deposition of new CENPA-containing nucleosomes at the centromere	1	52.9×	0.043	RUVBL1
Disorders of transmembrane transporters	1	46.4×	0.043	ABCG5
ER-Phagosome pathway	1	43.3×	0.043	SEC61A1
Deubiquitination	1	41.4×	0.043	RUVBL1
UCH proteinases	1	41.4×	0.043	RUVBL1
ABC-family protein mediated transport	1	40.5×	0.043	ABCG5
Formation of the beta-catenin:TCF transactivating complex	1	40.1×	0.043	RUVBL1
TCF dependent signaling in response to WNT	1	39.2×	0.043	RUVBL1
Signaling by WNT	1	37.3×	0.043	RUVBL1
Signaling by Nuclear Receptors	1	34.0×	0.043	ABCG5
SRP-dependent cotranslational protein targeting to membrane	1	33.4×	0.043	SEC61A1
DNA Repair	1	32.8×	0.043	RUVBL1
Metabolism of proteins	2	8.2×	0.043	SEC61A1, RUVBL1
Signal Transduction	2	6.8×	0.043	RUVBL1, ABCG5
Chromatin organization	1	27.2×	0.049	RUVBL1

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
pronephric nephron development	1	5617.3×	0.005	SEC61A1
negative regulation of intestinal phytosterol absorption	1	2808.7×	0.005	ABCG5
negative regulation of intestinal cholesterol absorption	1	2808.7×	0.005	ABCG5
sterol transport	1	936.2×	0.008	ABCG5
telomerase RNA localization to Cajal body	1	802.5×	0.008	RUVBL1
SRP-dependent cotranslational protein targeting to membrane	1	702.2×	0.008	SEC61A1
SRP-dependent cotranslational protein targeting to membrane, translocation	1	702.2×	0.008	SEC61A1
post-translational protein targeting to membrane, translocation	1	702.2×	0.008	SEC61A1
box C/D snoRNP assembly	1	561.7×	0.008	RUVBL1
cotranslational protein targeting to membrane	1	561.7×	0.008	SEC61A1
protein insertion into ER membrane	1	510.7×	0.008	SEC61A1
post-translational protein targeting to endoplasmic reticulum membrane	1	468.1×	0.008	SEC61A1
intestinal cholesterol absorption	1	468.1×	0.008	ABCG5
protein targeting to ER	1	374.5×	0.008	SEC61A1
positive regulation of telomere maintenance in response to DNA damage	1	374.5×	0.008	RUVBL1
regulation of DNA strand elongation	1	351.1×	0.008	RUVBL1
regulation of chromosome organization	1	312.1×	0.009	RUVBL1
response to muscle activity	1	193.7×	0.012	ABCG5
regulation of double-strand break repair	1	193.7×	0.012	RUVBL1
cholesterol efflux	1	175.5×	0.012	ABCG5
response to type II interferon	1	175.5×	0.012	SEC61A1
triglyceride homeostasis	1	160.5×	0.013	ABCG5
endoplasmic reticulum organization	1	140.4×	0.014	SEC61A1
response to ionizing radiation	1	137.0×	0.014	ABCG5
positive regulation of double-strand break repair via homologous recombination	1	127.7×	0.014	RUVBL1
regulation of DNA replication	1	122.1×	0.014	RUVBL1
positive regulation of DNA repair	1	119.5×	0.014	RUVBL1
DNA recombination	1	112.3×	0.014	RUVBL1
regulation of embryonic development	1	110.1×	0.014	RUVBL1
response to nutrient	1	98.5×	0.016	ABCG5

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RUVBL1	1	2
SEC61A1	0	0
ABCG5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	RUVBL1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RUVBL1	15	Binding:15
SEC61A1	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 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)
MOLIBRESIB	2	RUVBL1

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	1	RUVBL1
C	Druggable family + PDB, no drug	1	ABCG5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SEC61A1

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)
SEC61A1	7	—
ABCG5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.