Hereditary sensory and autonomic neuropathy type 4

Summary

Hereditary sensory and autonomic neuropathy type 4 (MONDO:0009746) is a disease caused by NTRK1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: NTRK1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 1,382
• Phenotypes (HPO): 56

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.14	Japan	Validated

Signs & symptoms

Clinical features (HPO)

56 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000742	Self-mutilation	Very frequent (80-99%)
HP:0000970	Anhidrosis	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0002726	Recurrent Staphylococcus aureus infections	Very frequent (80-99%)
HP:0002754	Osteomyelitis	Very frequent (80-99%)
HP:0003134	Abnormality of peripheral nerve conduction	Very frequent (80-99%)
HP:0007021	Pain insensitivity	Very frequent (80-99%)
HP:0010829	Impaired temperature sensition	Very frequent (80-99%)
HP:0011136	Aplasia of the sweat glands	Very frequent (80-99%)
HP:0000958	Dry skin	Frequent (30-79%)
HP:0000987	Atypical scarring of skin	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001954	Recurrent fever	Frequent (30-79%)
HP:0002661	Painless fractures due to injury	Frequent (30-79%)
HP:0002821	Neuropathic arthropathy	Frequent (30-79%)
HP:0003091	Trophic limb changes	Frequent (30-79%)
HP:0005368	Abnormality of humoral immunity	Frequent (30-79%)
HP:0006480	Premature loss of teeth	Frequent (30-79%)
HP:0012170	Nail-biting	Frequent (30-79%)
HP:0025615	Abscess	Frequent (30-79%)
HP:0100491	Abnormality of lower limb joint	Frequent (30-79%)
HP:0100537	Fasciitis	Frequent (30-79%)
HP:0100725	Lichenification	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0000736	Short attention span	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0000978	Bruising susceptibility	Occasional (5-29%)
HP:0001279	Syncope	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0001955	Unexplained fevers	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002100	Recurrent aspiration pneumonia	Occasional (5-29%)
HP:0002270	Abnormality of the autonomic nervous system	Occasional (5-29%)
HP:0002936	Distal sensory impairment	Occasional (5-29%)
HP:0003028	Abnormality of the ankles	Occasional (5-29%)
HP:0003095	Septic arthritis	Occasional (5-29%)
HP:0003272	Abnormality of the hip bone	Occasional (5-29%)
HP:0003474	Somatic sensory dysfunction	Occasional (5-29%)
HP:0004302	Functional motor deficit	Occasional (5-29%)
HP:0004926	Orthostatic hypotension due to autonomic dysfunction	Occasional (5-29%)
HP:0008000	Decreased corneal reflex	Occasional (5-29%)
HP:0009085	Alveolar ridge overgrowth	Occasional (5-29%)
HP:0010885	Avascular necrosis	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0030757	Tooth abscess	Occasional (5-29%)
HP:0030811	Tongue pain	Occasional (5-29%)
HP:0100710	Impulsivity	Occasional (5-29%)
HP:0100712	Abnormal lumbar spine morphology	Occasional (5-29%)
HP:0100851	Abnormal emotion/affect behavior	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary sensory and autonomic neuropathy type 4
Mondo ID	MONDO:0009746
OMIM	256800
Orphanet	642
DOID	DOID:0070146
ICD-11	1831234152
NCIT	C118633
SNOMED CT	62985007
UMLS	C0020074
MedGen	6915
GARD	0003006
NORD	1236
Is cancer (heuristic)	no

Also known as: CIP-anhidrosis syndrome · CIPA · congenital insensitivity to pain with anhidrosis · congenital insensitivity to pain-anhidrosis syndrome · hereditary sensory and autonomic neuropathy caused by mutation in NTRK1 · Hereditary Sensory and Autonomic Neuropathy Type IV · hereditary sensory and autonomic neuropathy type IV · HSAN IV · HSAN4 · HSNAN4 · insensitivity to pain, congenital, with anhidrosis · NTRK1 hereditary sensory and autonomic neuropathy

Data availability: 1,382 ClinVar variants · 4 GenCC gene-disease records · 12 cell lines.

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 4

Related subtypes (12): polyneuropathy-hand defect syndrome, 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 5, 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

600 retrieved; paginated sample, class counts are floors:

349 likely benign, 144 uncertain significance, 47 pathogenic, 17 likely pathogenic, 17 conflicting classifications of pathogenicity, 14 pathogenic/likely pathogenic, 9 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12304	NM_001012331.1(NTRK1):c.[25C>T;1792C>T;1820G>T]		Pathogenic	no assertion criteria provided
12305	NM_002529.4(NTRK1):c.[253C>A;429-1G>C]		Pathogenic	no assertion criteria provided
1070409	NM_002529.4(NTRK1):c.1877dup (p.Leu627fs)	NTRK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070814	NM_002529.4(NTRK1):c.2025_2026del (p.Tyr676fs)	NTRK1	Pathogenic	criteria provided, single submitter
1072190	NM_002529.4(NTRK1):c.229C>T (p.Gln77Ter)	NTRK1	Pathogenic	criteria provided, single submitter
1072893	NM_002529.4(NTRK1):c.1796_1803dup (p.Arg602fs)	NTRK1	Pathogenic	criteria provided, single submitter
1073315	NM_002529.4(NTRK1):c.575-19G>A	NTRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073488	NM_002529.4(NTRK1):c.989_990del (p.Thr330fs)	NTRK1	Pathogenic	criteria provided, single submitter
1074362	NM_002529.4(NTRK1):c.1649_1650insGGCAGGAAGTCGGCACTGAA (p.Ser550_Glu551insAlaGlySerArgHisTer)	NTRK1	Pathogenic	criteria provided, single submitter
1076078	NM_002529.4(NTRK1):c.2133G>A (p.Trp711Ter)	NTRK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076204	NM_002529.4(NTRK1):c.1294del (p.Leu432fs)	NTRK1	Pathogenic	criteria provided, single submitter
12301	NM_002529.4(NTRK1):c.2046+3A>C	NTRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12303	NM_002529.4(NTRK1):c.2339G>C (p.Arg780Pro)	NTRK1	Pathogenic	no assertion criteria provided
12310	NM_002529.4(NTRK1):c.2084C>T (p.Pro695Leu)	NTRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12312	NM_002529.4(NTRK1):c.1759A>G (p.Met587Val)	NTRK1	Pathogenic	criteria provided, single submitter
1284518	NM_002529.4(NTRK1):c.1805G>A (p.Arg602Gln)	NTRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1302927	NM_002529.4(NTRK1):c.429-1G>A	NTRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323379	NM_002529.4(NTRK1):c.1354+1G>A	NTRK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1388110	NM_002529.4(NTRK1):c.1804del (p.Arg602fs)	NTRK1	Pathogenic	criteria provided, single submitter
1391432	NM_002529.4(NTRK1):c.513del (p.Glu172fs)	NTRK1	Pathogenic	criteria provided, single submitter
1397970	NM_002529.4(NTRK1):c.2311C>T (p.Arg771Cys)	NTRK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1408081	NM_002529.4(NTRK1):c.595C>T (p.Gln199Ter)	NTRK1	Pathogenic	criteria provided, single submitter
1419925	NM_002529.4(NTRK1):c.1094del (p.Asn365fs)	NTRK1	Pathogenic	criteria provided, single submitter
1420732	NM_002529.4(NTRK1):c.850+1G>C	NTRK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1433100	NM_002529.4(NTRK1):c.1981G>T (p.Gly661Ter)	NTRK1	Pathogenic	criteria provided, single submitter
1441298	NM_002529.4(NTRK1):c.2078G>A (p.Trp693Ter)	NTRK1	Pathogenic	criteria provided, single submitter
1451941	NM_002529.4(NTRK1):c.1438G>T (p.Glu480Ter)	NTRK1	Pathogenic	criteria provided, single submitter
1453767	NM_002529.4(NTRK1):c.1298del (p.Ser433fs)	NTRK1	Pathogenic	criteria provided, single submitter
1455199	NC_000001.10:g.(?156837886)(156841557_?)del	NTRK1	Pathogenic	criteria provided, single submitter
1455865	NM_002529.4(NTRK1):c.1552del (p.Glu518fs)	NTRK1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · 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
NTRK1	Definitive	Autosomal recessive	hereditary sensory and autonomic neuropathy type 4	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NTRK1	Orphanet:146	Differentiated thyroid carcinoma
NTRK1	Orphanet:642	Hereditary sensory and autonomic neuropathy type 4
NTRK1	Orphanet:64752	Hereditary sensory and autonomic neuropathy type 5
NTRK1	Orphanet:99361	Isolated familial medullary thyroid carcinoma
HAX1	Orphanet:99749	Kostmann syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NTRK1	HGNC:8031	ENSG00000198400	P04629	High affinity nerve growth factor receptor	gencc,clinvar
HAX1	HGNC:16915	ENSG00000143575	O00165	HCLS1-associated protein X-1	clinvar
INSRR	HGNC:6093	ENSG00000027644	P14616	Insulin receptor-related protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NTRK1	High affinity nerve growth factor receptor	Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons.
HAX1	HCLS1-associated protein X-1	Recruits the Arp2/3 complex to the cell cortex and regulates reorganization of the cortical actin cytoskeleton via its interaction with KCNC3 and the Arp2/3 complex.
INSRR	Insulin receptor-related protein	Receptor with tyrosine-protein kinase activity.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Kinase	2	18.5×	0.008
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NTRK1	Kinase	yes	2.7.10.1	Cys-rich_flank_reg_C, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
HAX1	Other/Unknown	no		HAX-1
INSRR	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom

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
apex of heart	2
dorsal root ganglion	1
male germ line stem cell (sensu Vertebrata) in testis	1
heart right ventricle	1
hindlimb stylopod muscle	1
adult mammalian kidney	1
myocardium	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NTRK1	160	broad	marker	dorsal root ganglion, apex of heart, male germ line stem cell (sensu Vertebrata) in testis
HAX1	295	ubiquitous	marker	apex of heart, heart right ventricle, hindlimb stylopod muscle
INSRR	94	tissue_specific	marker	myocardium, skeletal muscle tissue of rectus abdominis, adult mammalian kidney

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NTRK1	9,181
HAX1	2,243
INSRR	1,866

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NTRK1	P04629	65
INSRR	P14616	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HAX1	O00165	60.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 3 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
TRKA activation by NGF	1	5710.0×	9e-04	NTRK1
PLC-gamma1 signalling	1	3806.7×	9e-04	NTRK1
Signalling to STAT3	1	3806.7×	9e-04	NTRK1
NGF-independant TRKA activation	1	2284.0×	9e-04	NTRK1
Signalling to p38 via RIT and RIN	1	2284.0×	9e-04	NTRK1
ARMS-mediated activation	1	1631.4×	0.001	NTRK1
PI3K/AKT activation	1	1268.9×	0.001	NTRK1
Frs2-mediated activation	1	951.7×	0.001	NTRK1
Retrograde neurotrophin signalling	1	815.7×	0.001	NTRK1
Signalling to RAS	1	671.8×	0.001	NTRK1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cell surface receptor protein tyrosine kinase signaling pathway	2	115.8×	0.004	NTRK1, INSRR
protein autophosphorylation	2	96.8×	0.004	NTRK1, INSRR
programmed cell death involved in cell development	1	2808.7×	0.004	NTRK1
cellular response to alkaline pH	1	2808.7×	0.004	INSRR
olfactory nerve development	1	1872.4×	0.004	NTRK1
behavioral response to formalin induced pain	1	1872.4×	0.004	NTRK1
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	2	52.2×	0.004	NTRK1, HAX1
response to hydrostatic pressure	1	1404.3×	0.005	NTRK1
granulocyte colony-stimulating factor signaling pathway	1	1123.5×	0.005	HAX1
mechanoreceptor differentiation	1	1123.5×	0.005	NTRK1
positive regulation of granulocyte differentiation	1	936.2×	0.005	HAX1
regulation of autophagy of mitochondrion	1	936.2×	0.005	HAX1
regulation of actin filament organization	1	802.5×	0.005	HAX1
cellular response to nicotine	1	702.2×	0.005	NTRK1
obsolete regulation of protein targeting to mitochondrion	1	702.2×	0.005	HAX1
peptidyl-tyrosine autophosphorylation	1	624.1×	0.006	NTRK1
axonogenesis involved in innervation	1	561.7×	0.006	NTRK1
male sex determination	1	468.1×	0.007	INSRR
nerve growth factor signaling pathway	1	432.1×	0.007	NTRK1
positive regulation of programmed cell death	1	374.5×	0.007	NTRK1
detection of mechanical stimulus involved in sensory perception of pain	1	374.5×	0.007	NTRK1
Sertoli cell development	1	374.5×	0.007	NTRK1
negative regulation of apoptotic process	2	23.2×	0.007	NTRK1, HAX1
neurotrophin TRK receptor signaling pathway	1	351.1×	0.007	NTRK1
sympathetic nervous system development	1	312.1×	0.007	NTRK1
positive regulation of Ras protein signal transduction	1	295.6×	0.007	NTRK1
detection of temperature stimulus involved in sensory perception of pain	1	280.9×	0.008	NTRK1
response to electrical stimulus	1	216.1×	0.009	NTRK1
positive regulation of synaptic transmission, glutamatergic	1	208.1×	0.009	NTRK1
regulation of actin filament polymerization	1	193.7×	0.010	HAX1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
NTRK1	PONATINIB
INSRR	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NTRK1	66	4
INSRR	16	4
HAX1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	NTRK1
FEDRATINIB	4	INSRR, NTRK1
AXITINIB	4	NTRK1
SORAFENIB	4	NTRK1
RUXOLITINIB	4	NTRK1
ENTRECTINIB	4	NTRK1
CABOZANTINIB	4	NTRK1
CERITINIB	4	NTRK1
BOSUTINIB	4	NTRK1
LORLATINIB	4	NTRK1
ABEMACICLIB	4	NTRK1
LAROTRECTINIB	4	NTRK1
LAROTRECTINIB SULFATE	4	NTRK1
REPOTRECTINIB	4	NTRK1
NINTEDANIB	4	INSRR, NTRK1
SUNITINIB	4	INSRR, NTRK1
QUIZARTINIB	4	NTRK1
CRIZOTINIB	4	INSRR, NTRK1
MIDOSTAURIN	4	NTRK1
AMITRIPTYLINE	4	NTRK1
NERATINIB	4	INSRR
BRIGATINIB	4	INSRR
CRENOLANIB	3	NTRK1
LINIFANIB	3	INSRR, NTRK1
DEFACTINIB	3	NTRK1
ENTOSPLETINIB	3	NTRK1
SITRAVATINIB	3	NTRK1
ALISERTIB	3	NTRK1
DOVITINIB	3	NTRK1
LESTAURTINIB	3	INSRR, NTRK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
NTRK1	1,194	Binding:1182, ADMET:7, Functional:5
INSRR	251	Binding:250, Functional:1
HAX1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NTRK1	2.7.10.1	receptor protein-tyrosine kinase
INSRR	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NTRK1	1,194
INSRR	251

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
PONATINIB	4	NTRK1
FEDRATINIB	4	INSRR, NTRK1
AXITINIB	4	NTRK1
SORAFENIB	4	NTRK1
RUXOLITINIB	4	NTRK1
ENTRECTINIB	4	NTRK1
CABOZANTINIB	4	NTRK1
CERITINIB	4	NTRK1
BOSUTINIB	4	NTRK1
LORLATINIB	4	NTRK1
ABEMACICLIB	4	NTRK1
LAROTRECTINIB	4	NTRK1
LAROTRECTINIB SULFATE	4	NTRK1
REPOTRECTINIB	4	NTRK1
NINTEDANIB	4	INSRR, NTRK1
SUNITINIB	4	INSRR, NTRK1
QUIZARTINIB	4	NTRK1
CRIZOTINIB	4	INSRR, NTRK1
MIDOSTAURIN	4	NTRK1
AMITRIPTYLINE	4	NTRK1
NERATINIB	4	INSRR
BRIGATINIB	4	INSRR
CRENOLANIB	3	NTRK1
LINIFANIB	3	INSRR, NTRK1
DEFACTINIB	3	NTRK1
ENTOSPLETINIB	3	NTRK1
SITRAVATINIB	3	NTRK1
ALISERTIB	3	NTRK1
DOVITINIB	3	NTRK1
LESTAURTINIB	3	INSRR, NTRK1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	NTRK1, INSRR
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	HAX1

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)
HAX1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.