Hereditary sensory and autonomic neuropathy type 5

Summary

Hereditary sensory and autonomic neuropathy type 5 (MONDO:0012092) is a disease caused by NGF (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: NGF (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 159
• Phenotypes (HPO): 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated
Point prevalence	<1 / 1 000 000	0.035	Japan	Not yet validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000168	Abnormality of the gingiva	Frequent (30-79%)
HP:0000272	Malar flattening	Frequent (30-79%)
HP:0000490	Deeply set eye	Frequent (30-79%)
HP:0000970	Anhidrosis	Frequent (30-79%)
HP:0001058	Poor wound healing	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0002661	Painless fractures due to injury	Frequent (30-79%)
HP:0007021	Pain insensitivity	Frequent (30-79%)
HP:0007249	Decreased number of small peripheral myelinated nerve fibers	Frequent (30-79%)
HP:0010829	Impaired temperature sensition	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary sensory and autonomic neuropathy type 5
Mondo ID	MONDO:0012092
OMIM	608654
Orphanet	64752
DOID	DOID:0070145
ICD-11	1411011731
SNOMED CT	128206006
UMLS	C0020075
MedGen	6916
GARD	0012328
Is cancer (heuristic)	no

Also known as: autosomal recessive hereditary sensory and autonomic neuropathy caused by mutation in NGF · congenital insensitivity to pain and thermal analgesia · hereditary sensory and autonomic neuropathy type V · HSAN V · HSAN5 · neuropathy, hereditary sensory and autonomic, type V · NGF autosomal recessive hereditary sensory and autonomic neuropathy

Data availability: 159 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › sensory peripheral neuropathy › hereditary sensory and autonomic neuropathy › hereditary sensory and autonomic neuropathy type 5

Related subtypes (12): polyneuropathy-hand defect syndrome, hereditary sensory and autonomic neuropathy type 4, neuropathy, hereditary sensory, atypical, X-linked hereditary sensory and autonomic neuropathy with hearing loss, hereditary sensory neuropathy X-linked, hereditary sensory and autonomic neuropathy type 6, hereditary sensory and autonomic neuropathy type 7, congenital insensitivity to pain-hypohidrosis syndrome, congenital insensitivity to pain with hyperhidrosis, hereditary sensory and autonomic neuropathy type 1, cold-induced sweating syndrome - hyperthermia spectrum, hereditary sensory and autonomic neuropathy type 2

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

159 retrieved; paginated sample, class counts are floors:

85 uncertain significance, 51 likely benign, 12 conflicting classifications of pathogenicity, 4 benign/likely benign, 3 benign, 2 likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2181214	NM_002506.3(NGF):c.241C>T (p.Arg81Ter)	NGF	Pathogenic	criteria provided, single submitter
29802	NM_002506.3(NGF):c.680_682delinsA (p.Thr227fs)	NGF	Pathogenic	criteria provided, single submitter
14045	NM_002506.3(NGF):c.661C>T (p.Arg221Trp)	NGF	Likely pathogenic	criteria provided, single submitter
804348	NM_001349253.2(SCN11A):c.2423C>A (p.Ala808Asp)	SCN11A	Likely pathogenic	criteria provided, single submitter
1028026	NM_002506.3(NGF):c.224G>A (p.Arg75Lys)	NGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1662263	NM_002506.3(NGF):c.553G>A (p.Val185Ile)	NGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245650	NM_002506.3(NGF):c.247C>T (p.Arg83Cys)	NGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291995	NM_002506.3(NGF):c.-13+14G>A	NGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
456626	NM_002506.3(NGF):c.170C>T (p.Ala57Val)	NGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
526751	NM_002506.3(NGF):c.174G>A (p.Ala58=)	NGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
526752	NM_002506.3(NGF):c.93C>G (p.Thr31=)	NGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
526753	NM_002506.3(NGF):c.165G>A (p.Pro55=)	NGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
876404	NM_002506.3(NGF):c.43G>A (p.Gly15Ser)	NGF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
291988	NM_002506.3(NGF):c.477G>A (p.Val159=)	NGF-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
456628	NM_002506.3(NGF):c.191C>T (p.Ala64Val)	NGF-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875323	NM_002506.3(NGF):c.552C>T (p.Pro184=)	NGF-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000642	NM_002506.3(NGF):c.388A>G (p.Arg130Gly)	NGF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1019949	NC_000001.10:g.(?115828681)(115829426_?)dup	NGF	Uncertain significance	criteria provided, single submitter
1024609	NM_002506.3(NGF):c.187G>A (p.Val63Met)	NGF	Uncertain significance	criteria provided, single submitter
1063239	NM_002506.3(NGF):c.572G>T (p.Gly191Val)	NGF	Uncertain significance	criteria provided, single submitter
1350197	NM_002506.3(NGF):c.124C>T (p.His42Tyr)	NGF	Uncertain significance	criteria provided, single submitter
1388445	NM_002506.3(NGF):c.487G>A (p.Val163Met)	NGF	Uncertain significance	criteria provided, single submitter
1388698	NM_002506.3(NGF):c.445G>T (p.Ala149Ser)	NGF	Uncertain significance	criteria provided, single submitter
1403014	NM_002506.3(NGF):c.361C>T (p.Arg121Trp)	NGF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1427446	NM_002506.3(NGF):c.280C>A (p.Pro94Thr)	NGF	Uncertain significance	criteria provided, single submitter
1440292	NM_002506.3(NGF):c.188T>C (p.Val63Ala)	NGF	Uncertain significance	criteria provided, single submitter
1465554	NM_002506.3(NGF):c.394G>A (p.Glu132Lys)	NGF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1468517	NM_002506.3(NGF):c.283C>T (p.Arg95Cys)	NGF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1468579	NM_002506.3(NGF):c.136A>G (p.Thr46Ala)	NGF	Uncertain significance	criteria provided, single submitter
1472973	NM_002506.3(NGF):c.222_223delinsAG (p.Arg75Gly)	NGF	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
NGF	Strong	Autosomal recessive	hereditary sensory and autonomic neuropathy	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NGF	Orphanet:64752	Hereditary sensory and autonomic neuropathy type 5
SCN11A	Orphanet:306577	Hereditary sodium channelopathy-related small fibers neuropathy
SCN11A	Orphanet:391392	Familial episodic pain syndrome with predominantly lower limb involvement
SCN11A	Orphanet:391397	Hereditary sensory and autonomic neuropathy type 7
SCN11A	Orphanet:46348	Paroxysmal extreme pain disorder
SCN11A	Orphanet:88642	Congenital insensitivity to pain-anosmia-neuropathic arthropathy
SCN11A	Orphanet:90026	Primary erythromelalgia

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NGF	HGNC:7808	ENSG00000134259	P01138	Beta-nerve growth factor	gencc,clinvar
SCN11A	HGNC:10583	ENSG00000168356	Q9UI33	Sodium channel protein type 11 subunit alpha	clinvar
NGF-AS1	HGNC:53922	ENSG00000228035		NGF antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NGF	Beta-nerve growth factor	Nerve growth factor is important for the development and maintenance of the sympathetic and sensory nervous systems.
SCN11A	Sodium channel protein type 11 subunit alpha	Sodium channel mediating the voltage-dependent sodium ion permeability of excitable membranes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	37.2×	0.053
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NGF	Other/Unknown	no		Nerve_growth_factor-rel, Nerve_growth_factor_CS, Nerve_growth_factor-like
SCN11A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_trans_assoc_dom
NGF-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	1
left uterine tube	1
right ovary	1
buccal mucosa cell	1
dorsal root ganglion	1
male germ line stem cell (sensu Vertebrata) in testis	1
descending thoracic aorta	1
left coronary artery	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NGF	158	broad	marker	cartilage tissue, left uterine tube, right ovary
SCN11A	166	broad	marker	buccal mucosa cell, dorsal root ganglion, male germ line stem cell (sensu Vertebrata) in testis
NGF-AS1	80		marker	descending thoracic aorta, thoracic aorta, left coronary artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NGF	3,968
SCN11A	1,202
NGF-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NGF	P01138	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SCN11A	Q9UI33	69.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TRKA activation by NGF	1	2855.0×	0.003	NGF
NFG and proNGF binds to p75NTR	1	2855.0×	0.003	NGF
PLC-gamma1 signalling	1	1903.3×	0.003	NGF
Ceramide signalling	1	1903.3×	0.003	NGF
Signalling to STAT3	1	1903.3×	0.003	NGF
NGF processing	1	1427.5×	0.003	NGF
Axonal growth stimulation	1	1427.5×	0.003	NGF
Signalling to p38 via RIT and RIN	1	1142.0×	0.003	NGF
p75NTR negatively regulates cell cycle via SC1	1	951.7×	0.003	NGF
NADE modulates death signalling	1	951.7×	0.003	NGF
ARMS-mediated activation	1	815.7×	0.003	NGF
PI3K/AKT activation	1	634.4×	0.004	NGF
Frs2-mediated activation	1	475.8×	0.004	NGF
p75NTR recruits signalling complexes	1	439.2×	0.004	NGF
NF-kB is activated and signals survival	1	439.2×	0.004	NGF
Retrograde neurotrophin signalling	1	407.9×	0.004	NGF
NRIF signals cell death from the nucleus	1	356.9×	0.004	NGF
Signalling to RAS	1	335.9×	0.004	NGF
Interaction between L1 and Ankyrins	1	184.2×	0.008	SCN11A
Phase 0 - rapid depolarisation	1	173.0×	0.008	SCN11A
NRAGE signals death through JNK	1	92.1×	0.014	NGF
L1CAM interactions	1	60.1×	0.020	SCN11A
Cardiac conduction	1	54.4×	0.021	SCN11A
Muscle contraction	1	38.6×	0.029	SCN11A
Axon guidance	1	22.6×	0.047	SCN11A
Nervous system development	1	21.5×	0.048	SCN11A
Developmental Biology	1	7.2×	0.134	SCN11A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sensory perception of pain	2	374.5×	4e-04	NGF, SCN11A
circadian rhythm	2	244.2×	5e-04	NGF, SCN11A
reflex	1	8426.0×	0.002	SCN11A
small intestine smooth muscle contraction	1	8426.0×	0.002	SCN11A
thermosensory behavior	1	4213.0×	0.002	SCN11A
behavioral response to acetic acid induced pain	1	4213.0×	0.002	SCN11A
response to high light intensity	1	2808.7×	0.002	SCN11A
positive regulation of neuron maturation	1	2808.7×	0.002	NGF
micturition	1	2808.7×	0.002	SCN11A
behavioral response to formalin induced pain	1	2808.7×	0.002	SCN11A
action potential initiation	1	2808.7×	0.002	SCN11A
thigmotaxis	1	2106.5×	0.002	SCN11A
response to nitric oxide	1	1685.2×	0.003	SCN11A
calcitonin gene-related peptide receptor signaling pathway	1	1404.3×	0.003	SCN11A
skeletal muscle organ development	1	1053.2×	0.004	SCN11A
positive regulation of collateral sprouting	1	936.2×	0.004	NGF
sensory perception of itch	1	936.2×	0.004	SCN11A
acute inflammatory response	1	842.6×	0.004	SCN11A
chronic inflammatory response	1	842.6×	0.004	SCN11A
membrane depolarization during action potential	1	842.6×	0.004	SCN11A
response to prostaglandin E	1	702.2×	0.004	SCN11A
artery development	1	702.2×	0.004	SCN11A
cAMP/PKA signal transduction	1	702.2×	0.004	SCN11A
nerve growth factor signaling pathway	1	648.1×	0.004	NGF
detection of mechanical stimulus involved in sensory perception of pain	1	561.7×	0.004	SCN11A
neurotrophin TRK receptor signaling pathway	1	526.6×	0.004	NGF
cellular response to cold	1	526.6×	0.004	SCN11A
nerve development	1	468.1×	0.004	NGF
regulation of release of sequestered calcium ion into cytosol	1	468.1×	0.004	NGF
positive regulation of Ras protein signal transduction	1	443.5×	0.005	NGF

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
SCN11A	IMIPRAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN11A	15	4
NGF	0	0
NGF-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMIPRAMINE	4	SCN11A
SERTINDOLE	4	SCN11A
PIMOZIDE	4	SCN11A
NIFEDIPINE	4	SCN11A
DILTIAZEM	4	SCN11A
MIBEFRADIL	4	SCN11A
HALOPERIDOL	4	SCN11A
MEXILETINE	4	SCN11A
AMITRIPTYLINE	4	SCN11A
AMIODARONE	4	SCN11A
CHLORPROMAZINE	4	SCN11A
TEDISAMIL	3	SCN11A
NITRENDIPINE	3	SCN11A
AJMALINE	3	SCN11A
CIFENLINE	2	SCN11A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN11A	33	Functional:16, Binding:15, ADMET:2
NGF	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

15 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	SCN11A
SERTINDOLE	4	SCN11A
PIMOZIDE	4	SCN11A
NIFEDIPINE	4	SCN11A
DILTIAZEM	4	SCN11A
MIBEFRADIL	4	SCN11A
HALOPERIDOL	4	SCN11A
MEXILETINE	4	SCN11A
AMITRIPTYLINE	4	SCN11A
AMIODARONE	4	SCN11A
CHLORPROMAZINE	4	SCN11A
TEDISAMIL	3	SCN11A
NITRENDIPINE	3	SCN11A
AJMALINE	3	SCN11A
CIFENLINE	2	SCN11A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN11A
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	2	NGF, NGF-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NGF	4	—
NGF-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.