Arthrogryposis, renal dysfunction, and cholestasis 2

Summary

Arthrogryposis, renal dysfunction, and cholestasis 2 (MONDO:0013255) is a disease caused by VIPAS39 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: VIPAS39 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 88

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arthrogryposis, renal dysfunction, and cholestasis 2
Mondo ID	MONDO:0013255
OMIM	613404
DOID	DOID:0111354
UMLS	C3150672
MedGen	462022
GARD	0015658
Is cancer (heuristic)	no

Also known as: ARCS2 · arthrogryposis, renal dysfunction, and cholestasis 2 · arthrogryposis, renal dysfunction, and cholestasis type 2 · arthrogryposis-renal dysfunction-cholestasis syndrome caused by mutation in VIPAS39 · VIPAS39 arthrogryposis-renal dysfunction-cholestasis syndrome

Data availability: 88 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › arthrogryposis-renal dysfunction-cholestasis syndrome › arthrogryposis, renal dysfunction, and cholestasis 2

Related subtypes (1): arthrogryposis, renal dysfunction, and cholestasis 1

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

88 retrieved; paginated sample, class counts are floors:

57 uncertain significance, 12 pathogenic, 8 conflicting classifications of pathogenicity, 8 likely pathogenic, 1 benign/likely benign, 1 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4280134	NC_000015.10:g.74805276A>G		Pathogenic	no assertion criteria provided
1075753	NM_001193315.2(VIPAS39):c.484C>T (p.Arg162Ter)	VIPAS39	Pathogenic	criteria provided, multiple submitters, no conflicts
111	NM_001193315.2(VIPAS39):c.535C>T (p.Gln179Ter)	VIPAS39	Pathogenic	no assertion criteria provided
112	NM_001193315.2(VIPAS39):c.749_753del (p.Thr250fs)	VIPAS39	Pathogenic	no assertion criteria provided
113	NM_001193315.2(VIPAS39):c.658C>T (p.Arg220Ter)	VIPAS39	Pathogenic	criteria provided, single submitter
114	NM_001193315.2(VIPAS39):c.871C>T (p.Gln291Ter)	VIPAS39	Pathogenic	no assertion criteria provided
115	NM_001193315.2(VIPAS39):c.2T>G (p.Met1Arg)	VIPAS39	Pathogenic	no assertion criteria provided
1701817	NM_001193315.2(VIPAS39):c.177_179delinsAAA (p.Trp59_Ser60delinsTer)	VIPAS39	Pathogenic	no assertion criteria provided
1701818	NM_001193315.2(VIPAS39):c.1141C>T (p.Arg381Ter)	VIPAS39	Pathogenic	criteria provided, single submitter
2572863	NM_001193315.2(VIPAS39):c.808C>T (p.Arg270Ter)	VIPAS39	Pathogenic	criteria provided, multiple submitters, no conflicts
4292097	NM_001193315.2(VIPAS39):c.344-2A>G	VIPAS39	Pathogenic	criteria provided, single submitter
501604	NM_001193315.2(VIPAS39):c.958C>T (p.Arg320Ter)	VIPAS39	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522399	NM_001193315.2(VIPAS39):c.1184G>A (p.Trp395Ter)	VIPAS39	Pathogenic	no assertion criteria provided
2582752	NM_001193315.2(VIPAS39):c.1048-1G>T	VIPAS39	Likely pathogenic	no assertion criteria provided
2690775	NM_001193315.2(VIPAS39):c.463_464del (p.Trp155fs)	VIPAS39	Likely pathogenic	criteria provided, single submitter
3377487	NM_001193315.2(VIPAS39):c.1048-1G>A	VIPAS39	Likely pathogenic	criteria provided, single submitter
3576809	NM_001193315.2(VIPAS39):c.837-2A>C	VIPAS39	Likely pathogenic	criteria provided, single submitter
3576827	NM_001193315.2(VIPAS39):c.166C>T (p.Arg56Ter)	VIPAS39	Likely pathogenic	criteria provided, single submitter
3576828	NM_001193315.2(VIPAS39):c.157_160del (p.Asp53fs)	VIPAS39	Likely pathogenic	criteria provided, single submitter
522398	NM_001193315.2(VIPAS39):c.677A>G (p.His226Arg)	VIPAS39	Likely pathogenic	no assertion criteria provided
627536	NM_001193315.2(VIPAS39):c.618_626dup (p.Arg206_Leu208dup)	VIPAS39	Likely pathogenic	criteria provided, single submitter
2044892	NM_001193315.2(VIPAS39):c.842C>G (p.Pro281Arg)	VIPAS39	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2177721	NM_001193315.2(VIPAS39):c.907A>G (p.Ile303Val)	VIPAS39	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2993683	NM_001193315.2(VIPAS39):c.93+9A>G	VIPAS39	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3576816	NM_001193315.2(VIPAS39):c.585C>T (p.Asn195=)	VIPAS39	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
498683	NM_001193315.2(VIPAS39):c.1455C>A (p.Ser485Arg)	VIPAS39	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
500636	NM_001193315.2(VIPAS39):c.15G>A (p.Lys5=)	VIPAS39	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
597174	NM_001193315.2(VIPAS39):c.171C>G (p.Val57=)	VIPAS39	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
713478	NM_001193315.2(VIPAS39):c.836+4A>G	VIPAS39	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028746	NM_001193315.2(VIPAS39):c.1003A>G (p.Thr335Ala)	VIPAS39	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
VIPAS39	Definitive	Autosomal recessive	arthrogryposis, renal dysfunction, and cholestasis 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VIPAS39	Orphanet:2697	Arthrogryposis-renal dysfunction-cholestasis syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VIPAS39	HGNC:20347	ENSG00000151445	Q9H9C1	Spermatogenesis-defective protein 39 homolog	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VIPAS39	Spermatogenesis-defective protein 39 homolog	Proposed to be involved in endosomal maturation implicating in part VPS33B.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VIPAS39	Other/Unknown	no		Vps16_C, Vps16_C_sf, Spe-39

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
ganglionic eminence	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VIPAS39	274	ubiquitous	marker	cortical plate, ganglionic eminence, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VIPAS39	1,242

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VIPAS39	Q9H9C1	78.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peptidyl-lysine hydroxylation	1	4213.0×	0.002	VIPAS39
vacuolar transport	1	2808.7×	0.002	VIPAS39
phagosome-lysosome fusion	1	1296.3×	0.002	VIPAS39
collagen metabolic process	1	1053.2×	0.002	VIPAS39
post-translational protein modification	1	421.3×	0.005	VIPAS39
endosome to lysosome transport	1	337.0×	0.005	VIPAS39
collagen fibril organization	1	224.7×	0.006	VIPAS39
intracellular protein transport	1	64.8×	0.019	VIPAS39
spermatogenesis	1	35.2×	0.032	VIPAS39
cell differentiation	1	29.1×	0.034	VIPAS39

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VIPAS39	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	VIPAS39

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
VIPAS39	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.