Arthrogryposis multiplex congenita 5

Summary

Arthrogryposis multiplex congenita 5 (MONDO:0100218) is a disease caused by TOR1A (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: TOR1A (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arthrogryposis multiplex congenita 5
Mondo ID	MONDO:0100218
OMIM	618947
DOID	DOID:0080981
UMLS	C5436453
MedGen	1731112
GARD	0026085
Is cancer (heuristic)	no

Also known as: AMC5 · ARTHROGRYPOSIS MULTIPLEX CONGENITA 5

Data availability: 18 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 › arthrogryposis multiplex congenita › arthrogryposis multiplex congenita 5

Related subtypes (23): prenatal-onset spinal muscular atrophy with congenital bone fractures, adducted thumbs-arthrogryposis syndrome, Christian type, arthrogryposis multiplex congenita 2, neurogenic type, fetal akinesia deformation sequence, arthrogryposis multiplex congenita-whistling face syndrome, arthrogryposis-hyperkeratosis syndrome, lethal form, multiple pterygium-malignant hyperthermia syndrome, Marden-Walker syndrome, arthrogryposis due to muscular dystrophy, infantile-onset X-linked spinal muscular atrophy, van den Ende-Gupta syndrome, lethal arthrogryposis-anterior horn cell disease syndrome, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, arthrogryposis-like syndrome, autosomal recessive myogenic arthrogryposis multiplex congenita, Wieacker-Wolff syndrome (spectrum), arthrogryposis multiplex congenita 6, arthrogryposis multiplex congenita 3, myogenic type, arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, microphthalmia microtia fetal akinesia, MYBPC1-related autosomal recessive non-lethal arthrogryposis multiplex congenita syndrome, hypomyelination neuropathy-arthrogryposis syndrome, arthrogryposis multiplex congenita 7, X-linked

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

18 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
4813706	NM_000113.3(TOR1A):c.349_352delinsTAGT (p.Glu117_Asn118delinsTer)	TOR1A	Pathogenic	criteria provided, single submitter
5180	NM_000113.3(TOR1A):c.904GAG[1] (p.Glu303del)	TOR1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
559927	NM_000113.3(TOR1A):c.862C>T (p.Arg288Ter)	TOR1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
974679	NM_000113.3(TOR1A):c.952G>A (p.Gly318Ser)	TOR1A	Pathogenic	no assertion criteria provided
2445982	NM_000113.3(TOR1A):c.844C>T (p.Arg282Ter)	TOR1A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3341475	NM_000113.3(TOR1A):c.287_288del (p.Leu96fs)	TOR1A	Likely pathogenic	criteria provided, single submitter
3377609	NM_000113.3(TOR1A):c.790_793del (p.Asp264fs)	TOR1A	Likely pathogenic	criteria provided, single submitter
3393413	NM_000113.3(TOR1A):c.486T>A (p.Cys162Ter)	TOR1A	Likely pathogenic	criteria provided, single submitter
4813705	NM_000113.3(TOR1A):c.621-2A>G	TOR1A	Likely pathogenic	criteria provided, single submitter
4845909	NM_000113.3(TOR1A):c.462G>A (p.Trp154Ter)	TOR1A	Likely pathogenic	criteria provided, single submitter
974680	NM_000113.3(TOR1A):c.961del (p.Thr321fs)	TOR1A	Likely pathogenic	criteria provided, single submitter
162491	NM_000113.3(TOR1A):c.863G>A (p.Arg288Gln)	TOR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1683721	NM_000113.3(TOR1A):c.20T>G (p.Val7Gly)	LOC130002772	Uncertain significance	criteria provided, multiple submitters, no conflicts
1212505	NM_000113.3(TOR1A):c.719T>C (p.Leu240Ser)	TOR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
2242340	NM_000113.3(TOR1A):c.304G>A (p.Gly102Arg)	TOR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
268214	NM_000113.3(TOR1A):c.385G>A (p.Val129Ile)	TOR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1694449	NM_000113.3(TOR1A):c.927A>C (p.Lys309Asn)	TOR1A	Likely benign	criteria provided, single submitter
5182	NM_000113.3(TOR1A):c.646G>C (p.Asp216His)	TOR1A	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 2 · 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
TOR1A	Definitive	Autosomal recessive	arthrogryposis multiplex congenita 5	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TOR1A	Orphanet:256	Early-onset generalized limb-onset dystonia
TOR1A	Orphanet:36899	Myoclonus-dystonia 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
TOR1A	HGNC:3098	ENSG00000136827	O14656	Torsin-1A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TOR1A	Torsin-1A	Protein with chaperone functions important for the control of protein folding, processing, stability and localization as well as for the reduction of misfolded protein aggregates.

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)
TOR1A	Other/Unknown	no		Torsin, Torsin_1/2, P-loop_NTPase

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
monocyte	1
secondary oocyte	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TOR1A	274	ubiquitous	marker	stromal cell of endometrium, secondary oocyte, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TOR1A	1,304

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TOR1A	O14656	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Cargo recognition for clathrin-mediated endocytosis	1	104.8×	0.010	TOR1A

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
synaptic vesicle membrane organization	1	3370.4×	0.002	TOR1A
positive regulation of synaptic vesicle endocytosis	1	2808.7×	0.002	TOR1A
regulation of dopamine uptake involved in synaptic transmission	1	2407.4×	0.002	TOR1A
nuclear membrane organization	1	2407.4×	0.002	TOR1A
regulation of protein localization to cell surface	1	1685.2×	0.002	TOR1A
protein deneddylation	1	1296.3×	0.002	TOR1A
wound healing, spreading of cells	1	1123.5×	0.002	TOR1A
nuclear envelope organization	1	991.3×	0.002	TOR1A
intermediate filament cytoskeleton organization	1	936.2×	0.002	TOR1A
synaptic vesicle transport	1	842.6×	0.002	TOR1A
protein localization to nucleus	1	351.1×	0.004	TOR1A
ERAD pathway	1	181.2×	0.007	TOR1A
response to oxidative stress	1	130.6×	0.009	TOR1A
neuron projection development	1	122.1×	0.009	TOR1A
protein folding	1	103.4×	0.010	TOR1A
cell adhesion	1	37.5×	0.027	TOR1A

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
TOR1A	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	TOR1A

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)
TOR1A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.