Achondroplasia

Summary

Achondroplasia (MONDO:0007037) is a disease caused by FGFR3 (GenCC Definitive), with 5 cohort genes and 46 clinical trials. Top therapeutic interventions include vosoritide, infigratinib, and somatropin.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: FGFR3 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 64
• Phenotypes (HPO): 39
• Clinical trials: 46

Clinical features

Epidemiology

Prevalence records

30 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	4.73	Worldwide	Validated
Prevalence at birth	1-9 / 100 000	3.62	Europe	Validated
Prevalence at birth	1-9 / 100 000	5.645	France	Validated
Prevalence at birth	1-9 / 100 000	3.7	Italy	Validated
Prevalence at birth	1-9 / 100 000	4.195	Sweden	Validated
Prevalence at birth	1-9 / 100 000	2.6466	Spain	Validated
Prevalence at birth	1-9 / 100 000	2.37	Denmark	Validated
Prevalence at birth	1-9 / 100 000	3.2	Latin America	Validated
Prevalence at birth	1-9 / 100 000	3.8	Australia	Validated
Prevalence at birth	1-9 / 100 000	3.63	Switzerland	Validated
Prevalence at birth	1-9 / 100 000	3.7877	United Kingdom	Validated
Prevalence at birth	1-9 / 100 000	6	Ukraine	Validated
Prevalence at birth	6-9 / 10 000	79.05	Iraq	Validated
Prevalence at birth	1-5 / 10 000	36.73	Iran, Islamic Republic of	Validated
Prevalence at birth	1-5 / 10 000	12.92	Kuwait	Validated
Prevalence at birth	1-5 / 10 000	25.87	Lebanon	Validated
Prevalence at birth	1-5 / 10 000	48.14	Saudi Arabia	Validated
Prevalence at birth	1-5 / 10 000	10.51	United Arab Emirates	Validated
Prevalence at birth	1-5 / 10 000	16.53	Cameroon	Validated
Prevalence at birth	1-9 / 100 000	4	North America	Validated

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0002808	Kyphosis	Very frequent (80-99%)
HP:0002979	Bowing of the legs	Very frequent (80-99%)
HP:0003498	Disproportionate short stature	Very frequent (80-99%)
HP:0005619	Thoracolumbar kyphosis	Very frequent (80-99%)
HP:0009826	Limb undergrowth	Very frequent (80-99%)
HP:0000242	Parietal bossing	Frequent (30-79%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000309	Abnormal midface morphology	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0001377	Limited elbow extension	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002870	Obstructive sleep apnea	Frequent (30-79%)
HP:0002938	Lumbar hyperlordosis	Frequent (30-79%)
HP:0003026	Short long bone	Frequent (30-79%)
HP:0003194	Short nasal bridge	Frequent (30-79%)
HP:0003416	Spinal canal stenosis	Frequent (30-79%)
HP:0004060	Trident hand	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0005819	Short middle phalanx of finger	Frequent (30-79%)
HP:0008445	Cervical spinal canal stenosis	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0010241	Short proximal phalanx of finger	Frequent (30-79%)
HP:0010536	Central sleep apnea	Frequent (30-79%)
HP:0011452	Functional abnormality of the middle ear	Frequent (30-79%)
HP:0045086	Knee joint hypermobility	Frequent (30-79%)
HP:0045087	Hip joint hypermobility	Frequent (30-79%)
HP:0000260	Wide anterior fontanel	Occasional (5-29%)
HP:0000956	Acanthosis nigricans	Occasional (5-29%)
HP:0001513	Obesity	Occasional (5-29%)
HP:0002091	Restrictive ventilatory defect	Occasional (5-29%)
HP:0003180	Flat acetabular roof	Occasional (5-29%)
HP:0003375	Narrow greater sciatic notch	Occasional (5-29%)
HP:0005257	Thoracic hypoplasia	Occasional (5-29%)
HP:0008905	Rhizomelia	Occasional (5-29%)
HP:0011867	Abnormality of the wing of the ilium	Occasional (5-29%)
HP:0012418	Hypoxemia	Occasional (5-29%)
HP:0000238	Hydrocephalus	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	achondroplasia
Mondo ID	MONDO:0007037
MeSH	D000130
OMIM	100800
Orphanet	15
DOID	DOID:4480
ICD-10-CM	Q77.4
ICD-11	24224082
NCIT	C34345
SNOMED CT	86268005
UMLS	C0001080
MedGen	1289
GARD	0008173
MedDRA	10000452
NORD	711
Is cancer (heuristic)	no

Also known as: ACH · achondroplasia · achondroplastic dwarfism

Data availability: 64 ClinVar variants · 7 GenCC gene-disease records · 31 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › achondroplasia

Related subtypes (49): atelosteogenesis, midface dysplasia, Kashin-Beck disease, Boomerang dysplasia, campomelic dysplasia, cleidocranial dysplasia 1, Leri-Weill dyschondrosteosis, hypochondroplasia, metaphyseal chondrodysplasia, Jansen type, Schmid metaphyseal chondrodysplasia, Kniest dysplasia, pseudoachondroplasia, ulna metaphyseal dysplasia syndrome, acheiropody, microcephalic osteodysplastic primordial dwarfism type I, microcephalic osteodysplastic primordial dwarfism type II, bone dysplasia, lethal Holmgren type, cleidocranial dysplasia, recessive form, diastrophic dysplasia, hypertrichotic osteochondrodysplasia Cantu type, lethal Kniest-like dysplasia, metaphyseal chondrodysplasia, Kaitila type, metaphyseal chondrodysplasia, Spahr type, metaphyseal chondrodysplasia-retinitis pigmentosa syndrome, pycnodysostosis, pyknoachondrogenesis, Pyle disease, schneckenbecken dysplasia, mesomelia-synostoses syndrome, lethal chondrodysplasia, Seller type, acrocapitofemoral dysplasia, brachyolmia, Desbuquois dysplasia, fibrochondrogenesis, multiple epiphyseal dysplasia, spondyloepiphyseal dysplasia, thanatophoric dysplasia, Blount disease, osteogenesis imperfecta, achondrogenesis, acromesomelic dysplasia, neonatal osteosclerotic dysplasia, Akaba Hayasaka syndrome, Fairbank disease, mesomelic dysplasia, spondyloepimetaphyseal dysplasia, cleidocranial dysplasia 2, arterial tortuosity-bone fragility syndrome, linkeropathy

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

64 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 15 pathogenic, 9 conflicting classifications of pathogenicity, 8 pathogenic/likely pathogenic, 6 benign/likely benign, 3 likely pathogenic, 1 not provided, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
441276	NM_000142.4(FGFR3):c.[1130T>G;1138G>A]		Pathogenic	no assertion criteria provided
803097	NM_000138.5(FBN1):c.1130G>A (p.Cys377Tyr)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16327	NM_000142.5(FGFR3):c.1138G>A (p.Gly380Arg)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16328	NM_000142.5(FGFR3):c.1138G>C (p.Gly380Arg)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16330	NM_000142.5(FGFR3):c.1123G>T (p.Gly375Cys)	FGFR3	Pathogenic	criteria provided, single submitter
16331	NM_000142.5(FGFR3):c.1948A>G (p.Lys650Glu)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16332	NM_000142.5(FGFR3):c.742C>T (p.Arg248Cys)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16335	NM_000142.5(FGFR3):c.2419T>A (p.Ter807Arg)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16337	NM_000142.5(FGFR3):c.1620C>A (p.Asn540Lys)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16338	NM_000142.5(FGFR3):c.1620C>G (p.Asn540Lys)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16339	NM_000142.5(FGFR3):c.746C>G (p.Ser249Cys)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16340	NM_000142.5(FGFR3):c.749C>G (p.Pro250Arg)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16341	NM_000142.5(FGFR3):c.1949A>T (p.Lys650Met)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16342	NM_000142.5(FGFR3):c.1118A>G (p.Tyr373Cys)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16347	NM_000142.5(FGFR3):c.1950G>C (p.Lys650Asn)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16349	NM_000142.5(FGFR3):c.1619A>G (p.Asn540Ser)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16356	NM_000142.5(FGFR3):c.835A>T (p.Ser279Cys)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
16358	NM_000142.5(FGFR3):c.251C>T (p.Ser84Leu)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16359	NM_000142.5(FGFR3):c.1108G>T (p.Gly370Cys)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
2203500	NM_000142.5(FGFR3):c.1031C>G (p.Ser344Cys)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
65562	NM_000142.5(FGFR3):c.2420G>T (p.Ter807Leu)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
65564	NM_000142.5(FGFR3):c.2421A>G (p.Ter807Trp)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
65855	NM_000142.5(FGFR3):c.1949A>C (p.Lys650Thr)	FGFR3	Pathogenic	criteria provided, multiple submitters, no conflicts
1332754	NM_000138.5:c.(?1317)(1837+1_1838-1)del	FBN1	Likely pathogenic	criteria provided, single submitter
1332776	NM_000142.5(FGFR3):c.1144G>A (p.Gly382Ser)	FGFR3	Likely pathogenic	criteria provided, single submitter
1679899	NM_000142.5(FGFR3):c.1183C>A (p.Leu395Ile)	FGFR3	Likely pathogenic	criteria provided, single submitter
1680012	NM_000142.5(FGFR3):c.473G>A (p.Arg158Gln)	FGFR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1680106	NM_000142.5(FGFR3):c.1827C>G (p.Ala609=)	FGFR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
221944	NM_000142.5(FGFR3):c.1879G>A (p.Glu627Lys)	FGFR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
255344	NM_000142.5(FGFR3):c.616-6G>A	FGFR3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 52 · Orphanet: 37 · 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
FGFR3	Definitive	Autosomal dominant	achondroplasia	52

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGFR3	Orphanet:15	Achondroplasia
FGFR3	Orphanet:1860	Thanatophoric dysplasia type 1
FGFR3	Orphanet:2363	Lacrimoauriculodentodigital syndrome
FGFR3	Orphanet:251576	Gliosarcoma
FGFR3	Orphanet:251579	Giant cell glioblastoma
FGFR3	Orphanet:35099	Non-syndromic bicoronal craniosynostosis
FGFR3	Orphanet:429	Hypochondroplasia
FGFR3	Orphanet:53271	Muenke syndrome
FGFR3	Orphanet:794	Saethre-Chotzen syndrome
FGFR3	Orphanet:85164	Camptodactyly-tall stature-scoliosis-hearing loss syndrome
FGFR3	Orphanet:85165	Severe achondroplasia-developmental delay-acanthosis nigricans syndrome
FGFR3	Orphanet:93262	Crouzon syndrome-acanthosis nigricans syndrome
FGFR3	Orphanet:93274	Thanatophoric dysplasia type 2
DMD	Orphanet:154	Familial isolated dilated cardiomyopathy
DMD	Orphanet:206546	Symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers
DMD	Orphanet:777	X-linked non-syndromic intellectual disability
DMD	Orphanet:98895	Becker muscular dystrophy
DMD	Orphanet:98896	Duchenne muscular dystrophy
FBN1	Orphanet:1885	Isolated ectopia lentis
FBN1	Orphanet:2084	Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome
FBN1	Orphanet:2462	Shprintzen-Goldberg syndrome
FBN1	Orphanet:2623	Geleophysic dysplasia
FBN1	Orphanet:2833	Stiff skin syndrome
FBN1	Orphanet:284963	Marfan syndrome type 1
FBN1	Orphanet:284979	Neonatal Marfan syndrome
FBN1	Orphanet:300382	Progeroid and marfanoid aspect-lipodystrophy syndrome
FBN1	Orphanet:3449	Weill-Marchesani syndrome
FBN1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
FBN1	Orphanet:969	Acromicric dysplasia
GATA4	Orphanet:251071	8p23.1 microdeletion syndrome
GATA4	Orphanet:251510	46,XY partial gonadal dysgenesis
GATA4	Orphanet:3303	Tetralogy of Fallot
GATA4	Orphanet:334	Hereditary atrial fibrillation
GATA4	Orphanet:576232	Partial atrioventricular septal defect with ventricular hypoplasia
GATA4	Orphanet:99067	Complete atrioventricular septal defect with ventricular hypoplasia
GATA4	Orphanet:99068	Complete atrioventricular septal defect-tetralogy of Fallot
GATA4	Orphanet:99103	Atrial septal defect, ostium secundum type

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FGFR3	HGNC:3690	ENSG00000068078	P22607	Fibroblast growth factor receptor 3	gencc,clinvar
CNP	HGNC:2158	ENSG00000173786	P09543	2’,3’-cyclic-nucleotide 3’-phosphodiesterase	clinvar
DMD	HGNC:2928	ENSG00000198947	P11532	Dystrophin	clinvar
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	clinvar
GATA4	HGNC:4173	ENSG00000136574	P43694	Transcription factor GATA-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGFR3	Fibroblast growth factor receptor 3	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis.
CNP	2’,3’-cyclic-nucleotide 3’-phosphodiesterase	Myelin-associated enzyme that catalyzes the phosphodiester hydrolysis of 2’,3’-cyclic nucleotides to 2’-nucleotides.
DMD	Dystrophin	Anchors the extracellular matrix to the cytoskeleton via F-actin.
FBN1	Fibrillin-1	Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues.
GATA4	Transcription factor GATA-4	Transcriptional activator that binds to the consensus sequence 5’-AGATAG-3’ and plays a key role in cardiac development and function.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.4

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	1	5.5×	0.336
Transcription factor	2	3.3×	0.336
Enzyme (other)	1	2.4×	0.471
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGFR3	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
CNP	Enzyme (other)	yes	3.1.4.37	CNPase, Cyclic_Pdiesterase, P-loop_NTPase
DMD	Transcription factor	no		Znf_ZZ, WW_dom, Actinin_actin-bd_CS
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
GATA4	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of hip	2
upper arm skin	1
upper leg skin	1
C1 segment of cervical spinal cord	1
inferior olivary complex	1
inferior vagus X ganglion	1
dorsal root ganglion	1
skeletal muscle tissue of rectus abdominis	1
trigeminal ganglion	1
decidua	1
synovial joint	1
duodenum	1
heart left ventricle	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGFR3	262	broad	marker	upper leg skin, skin of hip, upper arm skin
CNP	289	ubiquitous	marker	inferior olivary complex, inferior vagus X ganglion, C1 segment of cervical spinal cord
DMD	295	ubiquitous	marker	trigeminal ganglion, skeletal muscle tissue of rectus abdominis, dorsal root ganglion
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua
GATA4	85	broad	marker	right atrium auricular region, heart left ventricle, duodenum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GATA4	4,994
FGFR3	4,510
FBN1	3,640
DMD	2,479
CNP	1,715

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FGFR3	P22607	15
FBN1	P35555	11
DMD	P11532	6
GATA4	P43694	3
CNP	P09543	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 37. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
t(4;14) translocations of FGFR3	1	2855.0×	0.006	FGFR3
Signaling by FGFR3 fusions in cancer	1	2855.0×	0.006	FGFR3
Formation of lateral plate mesoderm	1	571.0×	0.016	GATA4
FGFR3b ligand binding and activation	1	407.9×	0.016	FGFR3
Signaling by activated point mutants of FGFR3	1	237.9×	0.016	FGFR3
FGFR3c ligand binding and activation	1	219.6×	0.016	FGFR3
Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	1	219.6×	0.016	GATA4
Phospholipase C-mediated cascade; FGFR3	1	219.6×	0.016	FGFR3
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	190.3×	0.016	GATA4
Transcriptional regulation of testis differentiation	1	178.4×	0.016	GATA4
Formation of definitive endoderm	1	178.4×	0.016	GATA4
Physiological factors	1	167.9×	0.016	GATA4
PI-3K cascade:FGFR3	1	158.6×	0.016	FGFR3
SHC-mediated cascade:FGFR3	1	150.3×	0.016	FGFR3
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	150.3×	0.016	GATA4
FRS-mediated FGFR3 signaling	1	135.9×	0.017	FGFR3
Signaling by FGFR3 in disease	1	124.1×	0.017	FGFR3
Negative regulation of FGFR3 signaling	1	109.8×	0.018	FGFR3
Cardiogenesis	1	105.7×	0.018	GATA4
Elastic fibre formation	1	84.0×	0.020	FBN1
TGF-beta receptor signaling activates SMADs	1	81.6×	0.020	FBN1
Molecules associated with elastic fibres	1	77.2×	0.020	FBN1
Striated Muscle Contraction	1	77.2×	0.020	DMD
Formation of the dystrophin-glycoprotein complex (DGC)	1	77.2×	0.020	DMD
Developmental Lineage of Pancreatic Acinar Cells	1	75.1×	0.020	GATA4
PI3K Cascade	1	68.0×	0.021	FGFR3
Developmental Lineage of Pancreatic Ductal Cells	1	57.1×	0.024	GATA4
Non-integrin membrane-ECM interactions	1	38.6×	0.034	DMD
Integrin cell surface interactions	1	33.6×	0.038	FBN1
Constitutive Signaling by Aberrant PI3K in Cancer	1	31.7×	0.038	FGFR3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cyclic nucleotide catabolic process	1	3370.4×	0.007	CNP
negative regulation of developmental growth	1	3370.4×	0.007	FGFR3
regulation of muscle system process	1	3370.4×	0.007	DMD
regulation of cellular response to growth factor stimulus	1	3370.4×	0.007	DMD
atrial septum secundum morphogenesis	1	1685.2×	0.007	GATA4
cardiac muscle cell action potential	1	1685.2×	0.007	DMD
fibroblast growth factor receptor apoptotic signaling pathway	1	1685.2×	0.007	FGFR3
embryonic heart tube anterior/posterior pattern specification	1	1123.5×	0.007	GATA4
post-embryonic eye morphogenesis	1	1123.5×	0.007	FBN1
bone maturation	1	1123.5×	0.007	FGFR3
atrioventricular valve formation	1	842.6×	0.007	GATA4
regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion	1	842.6×	0.007	DMD
obsolete sequestering of BMP in extracellular matrix	1	842.6×	0.007	FBN1
obsolete sequestering of TGFbeta in extracellular matrix	1	842.6×	0.007	FBN1
peptide biosynthetic process	1	842.6×	0.007	DMD
cardiac muscle tissue regeneration	1	842.6×	0.007	GATA4
skeletal system development	2	50.3×	0.007	FGFR3, FBN1
atrial septum primum morphogenesis	1	674.1×	0.008	GATA4
positive regulation of phospholipase activity	1	674.1×	0.008	FGFR3
negative regulation of osteoclast development	1	674.1×	0.008	FBN1
atrioventricular node development	1	561.7×	0.009	GATA4
regulation of skeletal muscle contraction	1	561.7×	0.009	DMD
cell growth involved in cardiac muscle cell development	1	481.5×	0.009	GATA4
cell-cell signaling	2	27.9×	0.009	FGFR3, GATA4
transdifferentiation	1	421.3×	0.010	GATA4
regulation of calcium ion transmembrane transport	1	421.3×	0.010	DMD
cardiac ventricle morphogenesis	1	374.5×	0.010	GATA4
endochondral bone growth	1	337.0×	0.010	FGFR3
embryonic foregut morphogenesis	1	337.0×	0.010	GATA4
atrioventricular canal development	1	306.4×	0.010	GATA4

Therapeutics

Drugs indicated for this disease

1 approved. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Vosoritide	Approved (phase 4)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Infigratinib.

Drug target analysis

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

Druggability breadth: 4 of 5 evidence-associated genes (80%) 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
FGFR3	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR3	64	4
CNP	0	0
DMD	0	0
FBN1	0	0
GATA4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	FGFR3
PEMIGATINIB	4	FGFR3
NINTEDANIB	4	FGFR3
FEDRATINIB	4	FGFR3
LENVATINIB	4	FGFR3
AXITINIB	4	FGFR3
SORAFENIB	4	FGFR3
INFIGRATINIB PHOSPHATE	4	FGFR3
INFIGRATINIB	4	FGFR3
ENTRECTINIB	4	FGFR3
CERITINIB	4	FGFR3
VANDETANIB	4	FGFR3
NINTEDANIB ESYLATE	4	FGFR3
BRIGATINIB	4	FGFR3
ERDAFITINIB	4	FGFR3
FUTIBATINIB	4	FGFR3
PAZOPANIB	4	FGFR3
SUNITINIB	4	FGFR3
DASATINIB	4	FGFR3
CRIZOTINIB	4	FGFR3
MIDOSTAURIN	4	FGFR3
LINIFANIB	3	FGFR3
SEMAXANIB	3	FGFR3
BRIVANIB	3	FGFR3
ALISERTIB	3	FGFR3
CEDIRANIB	3	FGFR3
DOVITINIB	3	FGFR3
LESTAURTINIB	3	FGFR3
TANDUTINIB	2	FGFR3
FORETINIB	2	FGFR3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
FGFR3	975	Binding:948, Functional:18, ADMET:9
GATA4	5	Binding:5
CNP	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FGFR3	2.7.10.1	receptor protein-tyrosine kinase
CNP	3.1.4.37, 3.1.4.58	2’,3’-cyclic-nucleotide 3’-phosphodiesterase, RNA 2’,3’-cyclic 3’-phosphodiesterase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
FGFR3	975

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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	FGFR3
PEMIGATINIB	4	FGFR3
NINTEDANIB	4	FGFR3
FEDRATINIB	4	FGFR3
LENVATINIB	4	FGFR3
AXITINIB	4	FGFR3
SORAFENIB	4	FGFR3
INFIGRATINIB PHOSPHATE	4	FGFR3
ENTRECTINIB	4	FGFR3
CERITINIB	4	FGFR3
VANDETANIB	4	FGFR3
NINTEDANIB ESYLATE	4	FGFR3
BRIGATINIB	4	FGFR3
ERDAFITINIB	4	FGFR3
FUTIBATINIB	4	FGFR3
PAZOPANIB	4	FGFR3
SUNITINIB	4	FGFR3
DASATINIB	4	FGFR3
CRIZOTINIB	4	FGFR3
MIDOSTAURIN	4	FGFR3
LINIFANIB	3	FGFR3
SEMAXANIB	3	FGFR3
BRIVANIB	3	FGFR3
ALISERTIB	3	FGFR3
CEDIRANIB	3	FGFR3
DOVITINIB	3	FGFR3
LESTAURTINIB	3	FGFR3
TANDUTINIB	2	FGFR3
FORETINIB	2	FGFR3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FGFR3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	CNP
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	DMD, FBN1, GATA4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CNP	1	—
DMD	0	—
FBN1	0	—
GATA4	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 46.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	19
PHASE2	16
PHASE3	4
PHASE2/PHASE3	3
PHASE1	2
PHASE4	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05353192	PHASE4	UNKNOWN	A Study to Evaluate the Efficacy and Safety of Recombinant Human Growth Hormone in Children With Achondroplasia
NCT03424018	PHASE3	ACTIVE_NOT_RECRUITING	An Extension Study to Evaluate the Efficacy and Safety of BMN 111 in Children With Achondroplasia
NCT05929807	PHASE2/PHASE3	ENROLLING_BY_INVITATION	A Clinical Trial to Investigate Long-term Safety, Tolerability, and Efficacy of Weekly Subcutaneous Doses With TransCon CNP in Children and Adolescents With Achondroplasia
NCT06926491	PHASE3	RECRUITING	Evaluate the Efficacy and Safety of KK8398 in Patients With Achondroplasia（AOBA Study）
NCT07441876	PHASE2/PHASE3	RECRUITING	Study to Evaluate the Efficacy and Safety of BMN 333 Versus Vosoritide in Children With Achondroplasia
NCT03197766	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of BMN 111 in Children With Achondroplasia
NCT05598320	PHASE2/PHASE3	COMPLETED	A Clinical Trial to Evaluate Efficacy and Safety of TransCon CNP Compared With Placebo in Children With Achondroplasia
NCT06164951	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Infigratinib in Children and Adolescents With Achondroplasia
NCT02724228	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate Long-Term Safety, Tolerability, & Efficacy of BMN 111 in Children With Achondroplasia (ACH)
NCT03989947	PHASE2	ACTIVE_NOT_RECRUITING	An Extension Study to Evaluate Safety and Efficacy of BMN 111 in Children With Achondroplasia
NCT04554940	PHASE2	ACTIVE_NOT_RECRUITING	A Clinical Trial to Evaluate Safety of Vosoritide in At-risk Infants With Achondroplasia
NCT05145010	PHASE2	ENROLLING_BY_INVITATION	Extension Study of Infigratinib in Children With Achondroplasia (ACH)
NCT06079398	PHASE2	RECRUITING	A Clinical Trial to Evaluate Efficacy and Safety of TransCon CNP Compared With Placebo in Infants (0 to <2 Years of Age) With Achondroplasia
NCT06433557	PHASE2	ACTIVE_NOT_RECRUITING	A Phase 2 Clinical Trial to Evaluate Efficacy, Safety, and Tolerability of Navepegritide in Combination With Lonapegsomatropin in Children With Achondroplasia
NCT06732895	PHASE2	RECRUITING	A Clinical Trial to Evaluate Efficacy and Safety of Navepegritide in Adolescents (12 - 18 Years of Age) With Achondroplasia.
NCT06842355	PHASE2	RECRUITING	A Study of TYRA-300 in Children With Achondroplasia: BEACH301
NCT07169279	PHASE2	RECRUITING	Interventional Study of Infigratinib in Children < 3 Years Old With Achondroplasia (ACH)
NCT07297875	PHASE1/PHASE2	NOT_YET_RECRUITING	A Study of ABSK061 to Assess Safety, Tolerability, Pharmacokinetics, and Efficacy in Children With Achondroplasia
NCT02055157	PHASE2	COMPLETED	A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia
NCT03583697	PHASE2	COMPLETED	A Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children With Achondroplasia
NCT04085523	PHASE2	COMPLETED	A Dose Escalation Trial Evaluating Safety, Efficacy, and Pharmacokinetics of TransCon CNP Administered Once Weekly in Prepubertal Children With Achondroplasia
NCT04265651	PHASE2	COMPLETED	Study of Infigratinib in Children With Achondroplasia
NCT04638153	PHASE2	TERMINATED	A Study Of Safety, Tolerability And Effectiveness Of Recifercept In Children With Achondroplasia
NCT05116046	PHASE2	TERMINATED	Continuation Study of Long-term Safety, Tolerability, Pharmacokinetics and Efficacy of Recifercept in Achondroplasia
NCT05246033	PHASE2	UNKNOWN	A Dose Escalation Trial Evaluating Safety, Efficacy, and Pharmacokinetics of Multiple Subcutaneous Doses of TransCon CNP Administered Once Weekly in Children With Achondroplasia
NCT01590446	PHASE1	COMPLETED	A Study to Evaluate Safety and Tolerability of BMN 111 Administered to Healthy Adult Volunteers
NCT05813314	PHASE1	TERMINATED	Bioequivalence Study to Compare Two Injection Devices for BMN 111 in Healthy Participants
NCT02597881	Not specified	RECRUITING	Achondroplasia Natural History Multicenter Clinical Study
NCT05328050	Not specified	RECRUITING	Registry for Patients With Achondroplasia / Hypochondroplasia (OMPR-Ach/Hy)
NCT06168201	Not specified	RECRUITING	VIrtual STudy in Achondroplasia for the US (VISTA)
NCT07301463	Not specified	RECRUITING	A Study in Children With Achondroplasia
NCT07388966	Not specified	RECRUITING	Prospective Longitudinal Monocentric Study to Measure Limb Movement in Patients With FGFR3-related Skeletal Dysplasia
NCT00001536	Not specified	COMPLETED	Issues Surrounding Prenatal Genetic Testing for Achondroplasia
NCT01435629	Not specified	COMPLETED	A Survey Collecting Data on Adult Height in Patients With Achondroplasia Treated With Somatropin
NCT01516229	Not specified	COMPLETED	Special Survey for Long Term Application
NCT01541306	Not specified	COMPLETED	C-Type Natriuretic Peptide and Achondroplasia
NCT01603095	Not specified	COMPLETED	A Multicenter, Multinational Clinical Assessment Study for Pediatric Patients With Achondroplasia
NCT03449368	Not specified	COMPLETED	Lifetime Impact of Achondroplasia Study in Europe-LIAISE
NCT03780153	Not specified	COMPLETED	The Norwegian Adult Achondroplasia Study
NCT03794609	Not specified	TERMINATED	Observational Study Investigating Clinical & Anthropometric Characteristics of Children With Achondroplasia.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
VOSORITIDE	4	7
INFIGRATINIB	4	3
SOMATROPIN	4	3
NAVEPEGRITIDE	2	6
RECIFERCEPT	2	3