Familial episodic pain syndrome with predominantly upper body involvement

Summary

Familial episodic pain syndrome with predominantly upper body involvement (MONDO:0014021) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		21	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	familial episodic pain syndrome with predominantly upper body involvement
Mondo ID	MONDO:0014021
OMIM	615040
Orphanet	391389
DOID	DOID:0111729
UMLS	C3808667
MedGen	814997
GARD	0017618
Is cancer (heuristic)	no

Also known as: episodic pain syndrome, familial, 1 · episodic pain syndrome, familial, type 1 · FEPS1

Data availability: 23 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › familial episodic pain syndrome › familial episodic pain syndrome with predominantly upper body involvement

Related subtypes (2): episodic pain syndrome, familial, 2, familial episodic pain syndrome with predominantly lower limb involvement

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

23 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 10 benign, 2 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
39602	NM_007332.3(TRPA1):c.2564A>G (p.Asn855Ser)	LOC126860417	Pathogenic	no assertion criteria provided
2673151	NM_007332.3(TRPA1):c.2755C>T (p.Arg919Ter)	LOC126860417	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2378253	NM_007332.3(TRPA1):c.1234G>A (p.Asp412Asn)	MSC-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2437337	NM_007332.3(TRPA1):c.1743del (p.Ser582fs)	MSC-AS1	Uncertain significance	criteria provided, single submitter
2571603	NM_007332.3(TRPA1):c.2065A>G (p.Met689Val)	MSC-AS1	Uncertain significance	criteria provided, single submitter
2690279	NM_007332.3(TRPA1):c.2581G>T (p.Val861Phe)	MSC-AS1	Uncertain significance	criteria provided, single submitter
3067888	NM_007332.3(TRPA1):c.2074A>C (p.Asn692His)	MSC-AS1	Uncertain significance	criteria provided, single submitter
3780748	NM_007332.3(TRPA1):c.1384T>C (p.Cys462Arg)	MSC-AS1	Uncertain significance	criteria provided, single submitter
689623	NM_007332.3(TRPA1):c.2194C>G (p.Pro732Ala)	MSC-AS1	Uncertain significance	criteria provided, single submitter
930526	NM_007332.3(TRPA1):c.2366C>T (p.Ala789Val)	MSC-AS1	Uncertain significance	criteria provided, single submitter
1034381	NM_007332.3(TRPA1):c.925C>T (p.His309Tyr)	TRPA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709462	NM_007332.3(TRPA1):c.1015G>A (p.Asp339Asn)	TRPA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4057248	NM_007332.3(TRPA1):c.901A>G (p.Ile301Val)	TRPA1	Uncertain significance	no assertion criteria provided
1342276	NM_007332.3(TRPA1):c.3053A>G (p.His1018Arg)	MSC-AS1	Benign	criteria provided, multiple submitters, no conflicts
1342277	NM_007332.3(TRPA1):c.2938-24C>G	MSC-AS1	Benign	criteria provided, multiple submitters, no conflicts
1342278	NM_007332.3(TRPA1):c.2938-49T>G	MSC-AS1	Benign	criteria provided, multiple submitters, no conflicts
1342279	NM_007332.3(TRPA1):c.2869-6C>A	MSC-AS1	Benign	criteria provided, multiple submitters, no conflicts
1342280	NM_007332.3(TRPA1):c.1905+28C>T	MSC-AS1	Benign	criteria provided, multiple submitters, no conflicts
1342282	NM_007332.3(TRPA1):c.1630C>T (p.Leu544=)	MSC-AS1	Benign	criteria provided, multiple submitters, no conflicts
1342283	NM_007332.3(TRPA1):c.1530-22T>C	MSC-AS1	Benign	criteria provided, multiple submitters, no conflicts
1239453	NM_007332.3(TRPA1):c.375T>C (p.Asn125=)	TRPA1	Benign	criteria provided, multiple submitters, no conflicts
1342281	NM_007332.3(TRPA1):c.1644+15C>T	TRPA1	Benign	criteria provided, multiple submitters, no conflicts
1342284	NM_007332.3(TRPA1):c.558A>C (p.Lys186Asn)	TRPA1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
TRPA1	Moderate	Autosomal dominant	familial episodic pain syndrome with predominantly upper body involvement	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRPA1	Orphanet:391389	Familial episodic pain syndrome with predominantly upper body involvement
TRPA1	Orphanet:581271	Cramp-fasciculation syndrome

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TRPA1	HGNC:497	ENSG00000104321	O75762	Transient receptor potential cation channel subfamily A member 1	gencc,clinvar
MSC-AS1	HGNC:48724	ENSG00000235531		MSC antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRPA1	Transient receptor potential cation channel subfamily A member 1	Ligand-activated Ca(2+)-permeable, nonselective cation channel involved in pain detection and possibly also in cold perception, oxygen concentration perception, cough, itch, and inner ear function.

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
Ion channel	1	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRPA1	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, Ankyrin_rpt-contain_sf
MSC-AS1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of urinary bladder	1
oocyte	1
secondary oocyte	1
right coronary artery	1
stromal cell of endometrium	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRPA1	167	broad	yes	oocyte, secondary oocyte, mucosa of urinary bladder
MSC-AS1	183	ubiquitous	marker	right coronary artery, stromal cell of endometrium, thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRPA1	2,451
MSC-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRPA1	O75762	17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
TRP channels	1	407.9×	0.002	TRPA1

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
cellular response to food	1	16852.0×	5e-04	TRPA1
regulation of blood circulation	1	16852.0×	5e-04	TRPA1
positive regulation of monoatomic anion transport	1	16852.0×	5e-04	TRPA1
cellular response to carbon dioxide	1	8426.0×	7e-04	TRPA1
thermoception	1	4213.0×	8e-04	TRPA1
detection of chemical stimulus involved in sensory perception of pain	1	4213.0×	8e-04	TRPA1
regulation of neuronal action potential	1	4213.0×	8e-04	TRPA1
urinary bladder smooth muscle contraction	1	2808.7×	0.001	TRPA1
cellular response to caffeine	1	1532.0×	0.002	TRPA1
calcium ion transmembrane import into cytosol	1	1532.0×	0.002	TRPA1
cellular response to toxic substance	1	1404.3×	0.002	TRPA1
detection of mechanical stimulus involved in sensory perception of pain	1	1123.5×	0.002	TRPA1
cellular response to cold	1	1053.2×	0.002	TRPA1
response to pain	1	887.0×	0.002	TRPA1
response to cold	1	561.7×	0.003	TRPA1
sensory perception of pain	1	374.5×	0.004	TRPA1
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	374.5×	0.004	TRPA1
cellular response to heat	1	343.9×	0.004	TRPA1
protein homotetramerization	1	237.3×	0.005	TRPA1
cellular response to hydrogen peroxide	1	234.1×	0.005	TRPA1
calcium ion transmembrane transport	1	210.7×	0.006	TRPA1
monoatomic ion transport	1	156.0×	0.007	TRPA1
intracellular calcium ion homeostasis	1	145.3×	0.007	TRPA1
response to xenobiotic stimulus	1	69.1×	0.015	TRPA1
cell surface receptor signaling pathway	1	64.1×	0.016	TRPA1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TRPA1	DICLOFENAC

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRPA1	23	4
MSC-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DICLOFENAC	4	TRPA1
MENTHOL	4	TRPA1
NICOTINE	4	TRPA1
MEFENAMIC ACID	4	TRPA1
DISULFIRAM	4	TRPA1
RESVERATROL	3	TRPA1
ICILLIN	3	TRPA1
LEVOMENTHOL	3	TRPA1
CANNABINOL	3	TRPA1
SALIRASIB	2	TRPA1
FLUFENAMIC ACID	2	TRPA1
TETRAHYDROCANNABIVARIN	2	TRPA1
CANNABIDIVARIN	2	TRPA1
CARVACROL	2	TRPA1
THYMOL	2	TRPA1
CHLORDANTOIN	2	TRPA1
ALLICIN	2	TRPA1
SANGUINARIUM	2	TRPA1
CANNABIGEROL	2	TRPA1
RG6341	2	TRPA1
URB-597	1	TRPA1
ALLYL ISOTHIOCYANATE	1	TRPA1
PLUMBAGIN	1	TRPA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TRPA1	344	Binding:289, Functional:49, ADMET:6

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TRPA1	344

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

23 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)
DICLOFENAC	4	TRPA1
MENTHOL	4	TRPA1
NICOTINE	4	TRPA1
MEFENAMIC ACID	4	TRPA1
DISULFIRAM	4	TRPA1
RESVERATROL	3	TRPA1
ICILLIN	3	TRPA1
LEVOMENTHOL	3	TRPA1
CANNABINOL	3	TRPA1
SALIRASIB	2	TRPA1
FLUFENAMIC ACID	2	TRPA1
TETRAHYDROCANNABIVARIN	2	TRPA1
CANNABIDIVARIN	2	TRPA1
CARVACROL	2	TRPA1
THYMOL	2	TRPA1
CHLORDANTOIN	2	TRPA1
ALLICIN	2	TRPA1
SANGUINARIUM	2	TRPA1
CANNABIGEROL	2	TRPA1
RG6341	2	TRPA1
URB-597	1	TRPA1
ALLYL ISOTHIOCYANATE	1	TRPA1
PLUMBAGIN	1	TRPA1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TRPA1
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	MSC-AS1

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)
MSC-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.