Primary erythermalgia

Summary

Primary erythermalgia (MONDO:0007571) is a disease caused by SCN9A (GenCC Definitive), with 2 cohort genes and 4 clinical trials. Top therapeutic interventions include emestedastat and funapide.

At a glance

• Prevalence: 1-9 / 100 000 (United States) [Orphanet-validated]
• Causal gene: SCN9A (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 269
• Phenotypes (HPO): 14
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	1.1	United States	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0010783	Erythema	Very frequent (80-99%)
HP:0032147	Erythromelalgia	Very frequent (80-99%)
HP:0000989	Pruritus	Frequent (30-79%)
HP:0001872	Abnormality of thrombocytes	Occasional (5-29%)
HP:0001909	Leukemia	Occasional (5-29%)
HP:0002045	Hypothermia	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002633	Vasculitis	Occasional (5-29%)
HP:0002936	Distal sensory impairment	Occasional (5-29%)
HP:0010741	Pedal edema	Occasional (5-29%)
HP:0012533	Allodynia	Occasional (5-29%)
HP:0012534	Dysesthesia	Occasional (5-29%)
HP:0200101	Decreased/absent ankle reflexes	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	primary erythermalgia
Mondo ID	MONDO:0007571
OMIM	133020
Orphanet	90026
ICD-11	327001486
NCIT	C125383
UMLS	C0014805
MedGen	8688
GARD	0006377
Is cancer (heuristic)	no

Also known as: Mitchell disease (formerly) · neuropathy, small fibre · PERYTHM · primary erythromelalgia · small fibre neuropathy

Data availability: 269 ClinVar variants · 3 GenCC gene-disease records · 14 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › erythromelalgia › primary erythermalgia

Related subtypes (1): secondary erythromelalgia

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

269 retrieved; paginated sample, class counts are floors:

107 uncertain significance, 64 conflicting classifications of pathogenicity, 46 benign, 30 benign/likely benign, 8 pathogenic, 4 likely pathogenic, 4 likely benign, 4 not provided, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1686173	NM_001365536.1(SCN9A):c.3452dup (p.Glu1152fs)	SCN1A-AS1	Pathogenic	criteria provided, single submitter
471143	NM_001365536.1(SCN9A):c.5351del (p.Glu1784fs)	SCN1A-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
538468	NM_001365536.1(SCN9A):c.1198G>A (p.Val400Met)	SCN1A-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
6349	NM_001365536.1(SCN9A):c.2606T>A (p.Leu869His)	SCN1A-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
6350	NM_001365536.1(SCN9A):c.2576T>C (p.Ile859Thr)	SCN1A-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
421969	NM_001365536.1(SCN9A):c.2719C>T (p.Arg907Trp)	SCN9A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6352	NM_001365536.1(SCN9A):c.4378T>G (p.Phe1460Val)	SCN9A	Pathogenic	no assertion criteria provided
6364	NM_001365536.1(SCN9A):c.2605C>T (p.Leu869Phe)	SCN9A	Pathogenic	no assertion criteria provided
6365	NM_001365536.1(SCN9A):c.647T>C (p.Phe216Ser)	SCN9A	Pathogenic	no assertion criteria provided
915877	NM_001365536.1(SCN9A):c.701T>C (p.Ile234Thr)	SCN9A	Pathogenic	criteria provided, single submitter
1028064	NM_001365536.1(SCN9A):c.901A>T (p.Lys301Ter)	SCN9A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
21345	NM_001365536.1(SCN9A):c.2501T>G (p.Leu834Arg)	SCN9A	Likely pathogenic	criteria provided, single submitter
2442090	NM_001365536.1(SCN9A):c.2656C>G (p.Gln886Glu)	SCN9A	Likely pathogenic	criteria provided, single submitter
3572929	NM_001365536.1(SCN9A):c.2680del (p.Glu894fs)	SCN9A	Likely pathogenic	criteria provided, single submitter
130260	NM_001365536.1(SCN9A):c.3002A>G (p.Tyr1001Cys)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130265	NM_001365536.1(SCN9A):c.3767A>G (p.Asn1256Ser)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
130272	NM_001365536.1(SCN9A):c.4923T>C (p.Leu1641=)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157597	NM_001365536.1(SCN9A):c.2248A>G (p.Ile750Val)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193648	NM_001365536.1(SCN9A):c.1238T>C (p.Ile413Thr)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193859	NM_001365536.1(SCN9A):c.1555G>A (p.Glu519Lys)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195488	NM_001365536.1(SCN9A):c.3684T>C (p.Tyr1228=)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195592	NM_001365536.1(SCN9A):c.3832C>G (p.Leu1278Val)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195676	NM_001365536.1(SCN9A):c.4073G>A (p.Arg1358Gln)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195816	NM_001365536.1(SCN9A):c.4314C>T (p.Val1438=)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234820	NM_001365536.1(SCN9A):c.5711G>A (p.Arg1904His)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
258885	NM_001365536.1(SCN9A):c.3402G>T (p.Leu1134Phe)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291185	NM_001365536.1(SCN9A):c.1464C>T (p.Leu488=)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30357	NM_001365536.1(SCN9A):c.2192T>A (p.Ile731Lys)	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331914	NM_001365536.1(SCN9A):c.*2228G>T	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
331915	NM_001365536.1(SCN9A):c.*2226T>G	SCN1A-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 7 · 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
SCN9A	Definitive	Autosomal dominant	primary erythermalgia	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN9A	Orphanet:306577	Hereditary sodium channelopathy-related small fibers neuropathy
SCN9A	Orphanet:33069	Dravet syndrome
SCN9A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN9A	Orphanet:46348	Paroxysmal extreme pain disorder
SCN9A	Orphanet:88642	Congenital insensitivity to pain-anosmia-neuropathic arthropathy
SCN9A	Orphanet:90026	Primary erythromelalgia
SCN9A	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2

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
SCN9A	HGNC:10597	ENSG00000169432	Q15858	Sodium channel protein type 9 subunit alpha	gencc,clinvar
SCN1A-AS1	HGNC:54069	ENSG00000236107		SCN1A and SCN9A antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN9A	Sodium channel protein type 9 subunit alpha	Pore-forming subunit of Nav1.7, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.

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)
SCN9A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SCN1A-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	2
dorsal root ganglion	1
stromal cell of endometrium	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN9A	187	ubiquitous	marker	sural nerve, dorsal root ganglion, stromal cell of endometrium
SCN1A-AS1	129	tissue_specific	marker	sural nerve, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCN9A	1,575
SCN1A-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN9A	Q15858	43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Interaction between L1 and Ankyrins	1	368.4×	0.010	SCN9A
Phase 0 - rapid depolarisation	1	346.1×	0.010	SCN9A
Sensory perception of taste	1	335.9×	0.010	SCN9A
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	278.5×	0.010	SCN9A
L1CAM interactions	1	120.2×	0.017	SCN9A
Cardiac conduction	1	108.8×	0.017	SCN9A
Sensory Perception	1	95.2×	0.017	SCN9A
Muscle contraction	1	77.2×	0.018	SCN9A
Axon guidance	1	45.1×	0.026	SCN9A
Nervous system development	1	42.9×	0.026	SCN9A
Developmental Biology	1	14.5×	0.069	SCN9A

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
action potential propagation	1	16852.0×	7e-04	SCN9A
detection of mechanical stimulus involved in sensory perception	1	2808.7×	0.002	SCN9A
behavioral response to pain	1	887.0×	0.003	SCN9A
detection of temperature stimulus involved in sensory perception of pain	1	842.6×	0.003	SCN9A
cardiac muscle cell action potential involved in contraction	1	702.2×	0.003	SCN9A
neuronal action potential	1	481.5×	0.004	SCN9A
sensory perception of pain	1	374.5×	0.005	SCN9A
circadian rhythm	1	244.2×	0.005	SCN9A
response to toxic substance	1	210.7×	0.005	SCN9A
post-embryonic development	1	205.5×	0.005	SCN9A
sodium ion transmembrane transport	1	203.0×	0.005	SCN9A
inflammatory response	1	37.7×	0.027	SCN9A

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
SCN9A	IMIPRAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN9A	36	4
SCN1A-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMIPRAMINE	4	SCN9A
SERTINDOLE	4	SCN9A
PIMOZIDE	4	SCN9A
NIFEDIPINE	4	SCN9A
DILTIAZEM	4	SCN9A
MIBEFRADIL	4	SCN9A
HALOPERIDOL	4	SCN9A
MEXILETINE	4	SCN9A
AMITRIPTYLINE	4	SCN9A
AMIODARONE	4	SCN9A
CHLORPROMAZINE	4	SCN9A
CARBAMAZEPINE	4	SCN9A
MEXILETINE HYDROCHLORIDE	4	SCN9A
CANNABIDIOL	4	SCN9A
SAFINAMIDE	4	SCN9A
LACOSAMIDE	4	SCN9A
TETRACAINE	4	SCN9A
LAMOTRIGINE	4	SCN9A
RILUZOLE	4	SCN9A
LIDOCAINE	4	SCN9A
TEDISAMIL	3	SCN9A
NITRENDIPINE	3	SCN9A
AJMALINE	3	SCN9A
RALFINAMIDE	3	SCN9A
VIXOTRIGINE	3	SCN9A
ELECLAZINE	3	SCN9A
TETRODOTOXIN	3	SCN9A
CIFENLINE	2	SCN9A
PF-05089771	2	SCN9A
PF-04531083	2	SCN9A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN9A	428	Binding:395, Functional:29, ADMET:3, Toxicity:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN9A	428

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

30 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)
IMIPRAMINE	4	SCN9A
SERTINDOLE	4	SCN9A
PIMOZIDE	4	SCN9A
NIFEDIPINE	4	SCN9A
DILTIAZEM	4	SCN9A
MIBEFRADIL	4	SCN9A
HALOPERIDOL	4	SCN9A
MEXILETINE	4	SCN9A
AMITRIPTYLINE	4	SCN9A
AMIODARONE	4	SCN9A
CHLORPROMAZINE	4	SCN9A
CARBAMAZEPINE	4	SCN9A
MEXILETINE HYDROCHLORIDE	4	SCN9A
CANNABIDIOL	4	SCN9A
SAFINAMIDE	4	SCN9A
LACOSAMIDE	4	SCN9A
TETRACAINE	4	SCN9A
LAMOTRIGINE	4	SCN9A
RILUZOLE	4	SCN9A
LIDOCAINE	4	SCN9A
TEDISAMIL	3	SCN9A
NITRENDIPINE	3	SCN9A
AJMALINE	3	SCN9A
RALFINAMIDE	3	SCN9A
VIXOTRIGINE	3	SCN9A
ELECLAZINE	3	SCN9A
TETRODOTOXIN	3	SCN9A
CIFENLINE	2	SCN9A
PF-05089771	2	SCN9A
PF-04531083	2	SCN9A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN9A
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	SCN1A-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)
SCN1A-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	2
PHASE1	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01090622	PHASE1/PHASE2	COMPLETED	Study of XPF-001 in the Treatment of Pain From Primary/Inherited Erythromelalgia (IEM)
NCT01486446	PHASE1/PHASE2	COMPLETED	Phase 2a, Exploratory Study to Evaluate the Safety, Efficacy, Tolerability and Pharmacokinetics of XPF-002 in Patients With Primary/Inherited Erythromelalgia
NCT03830762	PHASE1	COMPLETED	Xanamem™ in Healthy Elderly Subjects
NCT01160887	Not specified	COMPLETED	Diabetes Peripheral Neuropathy and Small-fibre Nerve Damage: A Comparative Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EMESTEDASTAT	2	1
FUNAPIDE	2	1