Usher syndrome, type 4

Summary

Usher syndrome, type 4 (MONDO:0029141) is a disease caused by ARSG (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ARSG (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Usher syndrome, type 4
Mondo ID	MONDO:0029141
OMIM	618144
UMLS	C4748364
MedGen	1648315
GARD	0025504
Is cancer (heuristic)	no

Also known as: USH4 · Usher syndrome, type IV

Data availability: 20 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Usher syndrome › Usher syndrome, type 4

Related subtypes (4): Usher syndrome type 1, retinitis pigmentosa-deafness syndrome, Usher syndrome type 2, Usher syndrome type 3

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

20 retrieved; paginated sample, class counts are floors:

8 pathogenic, 4 likely pathogenic, 3 benign, 2 uncertain significance, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1016642	NM_001267727.2(ARSG):c.983-2_983-1del	ARSG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065124	NM_001267727.2(ARSG):c.1270C>T (p.Arg424Cys)	ARSG	Pathogenic	no assertion criteria provided
2576530	NM_001267727.2(ARSG):c.1212+1G>A	ARSG	Pathogenic	no assertion criteria provided
2576531	NM_001267727.2(ARSG):c.275T>C (p.Leu92Pro)	ARSG	Pathogenic	no assertion criteria provided
2576532	NM_001267727.2(ARSG):c.588C>A (p.Tyr196Ter)	ARSG	Pathogenic	no assertion criteria provided
2576533	NM_001267727.2(ARSG):c.705-3940_982+2952del	ARSG	Pathogenic	no assertion criteria provided
585252	NM_001267727.2(ARSG):c.133G>T (p.Asp45Tyr)	ARSG	Pathogenic	no assertion criteria provided
992583	NM_001267727.2(ARSG):c.1326del (p.Ser443fs)	ARSG	Pathogenic	criteria provided, single submitter
992638	NM_001267727.2(ARSG):c.338G>A (p.Gly113Asp)	ARSG	Pathogenic	criteria provided, single submitter
1705705	NM_001267727.2(ARSG):c.982+1G>C	ARSG	Likely pathogenic	criteria provided, single submitter
3251973	NM_001267727.2(ARSG):c.407-2A>C	ARSG	Likely pathogenic	criteria provided, single submitter
3780049	NM_001267727.2(ARSG):c.821G>A (p.Trp274Ter)	ARSG	Likely pathogenic	criteria provided, single submitter
961169	NM_001267727.2(ARSG):c.253T>C (p.Ser85Pro)	ARSG	Likely pathogenic	criteria provided, single submitter
1002820	NM_001267727.2(ARSG):c.130G>A (p.Asp44Asn)	ARSG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1936064	NM_001267727.2(ARSG):c.1024C>T (p.Arg342Trp)	ARSG	Uncertain significance	criteria provided, single submitter
2412753	NM_001267727.2(ARSG):c.663_664del (p.Lys222fs)	ARSG	Uncertain significance	criteria provided, single submitter
1165514	NM_001267727.2(ARSG):c.765T>C (p.Pro255=)	ARSG	Benign	criteria provided, multiple submitters, no conflicts
1166453	NM_001267727.2(ARSG):c.707C>G (p.Thr236Ser)	ARSG	Benign	criteria provided, multiple submitters, no conflicts
1166454	NM_001267727.2(ARSG):c.820T>C (p.Trp274Arg)	ARSG	Benign	criteria provided, multiple submitters, no conflicts
782609	NM_001267727.2(ARSG):c.1092-5C>T	ARSG	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
ARSG	Strong	Autosomal recessive	Usher syndrome, type 4	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARSG	Orphanet:231183	Usher syndrome type 3

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
ARSG	HGNC:24102	ENSG00000141337	Q96EG1	Arylsulfatase G	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARSG	Arylsulfatase G	Displays arylsulfatase activity at acidic pH towards artificial substrates, such as p-nitrocatechol sulfate and also, but with a lower activity towards p-nitrophenyl sulfate and 4-methylumbelliferyl sulfate.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Phosphatase	1	83.9×	0.012

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARSG	Phosphatase	yes		Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS

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
blood	1
monocyte	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARSG	135	ubiquitous	marker	blood, stromal cell of endometrium, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARSG	1,175

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARSG	Q96EG1	91.90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
The activation of arylsulfatases	1	878.5×	0.008	ARSG
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	423.0×	0.008	ARSG
Glycosphingolipid metabolism	1	300.5×	0.008	ARSG
Glycosphingolipid catabolism	1	292.8×	0.008	ARSG
Sphingolipid metabolism	1	167.9×	0.011	ARSG
Metabolism of lipids	1	31.6×	0.048	ARSG
Post-translational protein modification	1	19.2×	0.067	ARSG
Metabolism of proteins	1	12.4×	0.086	ARSG
Metabolism	1	11.6×	0.086	ARSG

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
sulfur compound metabolic process	1	1123.5×	0.003	ARSG
glial cell differentiation	1	887.0×	0.003	ARSG
homeostasis of number of cells	1	674.1×	0.003	ARSG
lysosome organization	1	306.4×	0.005	ARSG
retina development in camera-type eye	1	255.3×	0.005	ARSG
neuron apoptotic process	1	185.2×	0.006	ARSG
gene expression	1	79.9×	0.013	ARSG

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
ARSG	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
ARSG	2	Binding:2

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	1	ARSG
E	Difficult family or no structure, no drug	0

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)
ARSG	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.