Dandy-Walker syndrome

Summary

Dandy-Walker syndrome (MONDO:0009072) is a disease with 17 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 17
• ClinVar variants: 19
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2.1	Europe	Validated
Prevalence at birth	1-9 / 100 000	1	Europe	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000238	Hydrocephalus	Very frequent (80-99%)
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000269	Prominent occiput	Very frequent (80-99%)
HP:0001305	Dandy-Walker malformation	Very frequent (80-99%)
HP:0002691	Platybasia	Very frequent (80-99%)
HP:0001321	Cerebellar hypoplasia	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002198	Dilated fourth ventricle	Frequent (30-79%)
HP:0005445	Enlarged posterior fossa	Frequent (30-79%)
HP:0006817	Aplasia/Hypoplasia of the cerebellar vermis	Frequent (30-79%)
HP:0010952	Mild fetal ventriculomegaly	Frequent (30-79%)
HP:0011427	Enlarged fetal cisterna magna	Frequent (30-79%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0002084	Encephalocele	Occasional (5-29%)
HP:0002516	Increased intracranial pressure	Occasional (5-29%)
HP:0007370	Aplasia/Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0000639	Nystagmus	Very rare (<1-4%)
HP:0002078	Truncal ataxia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Dandy-Walker syndrome
Mondo ID	MONDO:0009072
EFO	EFO:1000890
MeSH	D003616
OMIM	220200
Orphanet	217
DOID	DOID:2785
ICD-11	993088960
NCIT	C75012
SNOMED CT	14447001
UMLS	C0010964
MedGen	4150
GARD	0006242
MedDRA	10048411
NORD	1032
Is cancer (heuristic)	no

Also known as: Dandy Walker Malformation · Dandy-Walker complex · Dandy-Walker syndrome · Dandy-Walker syndrome or malformation (type of DW complex) · Dandy-Walker syndrome, Isolated cases · Dandy-Walker variant (type of DW complex) · DW complex · DWS · mega cisterna magna (type of DW complex)

Data availability: 19 ClinVar variants · 1 GenCC gene-disease record · 3 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › cerebellar disorder › Dandy-Walker syndrome

Related subtypes (4): cerebellar neoplasm, Miller Fisher syndrome, Behrens Baumann dust syndrome, cerebellar degeneration

Subtypes (3): isolated Dandy-Walker malformation with hydrocephalus, isolated Dandy-Walker malformation without hydrocephalus, Dandy-Walker malformation with nasopharyngeal teratoma and diaphragmatic hernia

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

19 retrieved; paginated sample, class counts are floors:

5 pathogenic/likely pathogenic, 5 pathogenic, 4 likely pathogenic, 4 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
427932	NM_001352754.2(ARMC9):c.1027C>T (p.Arg343Cys)	ARMC9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183349	NM_001384125.1(BLTP1):c.1557T>A (p.Tyr519Ter)	BLTP1	Pathogenic	criteria provided, single submitter
13980	NM_004333.6(BRAF):c.1600G>C (p.Gly534Arg)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183359	NM_001383.6(DPH1):c.686T>C (p.Leu229Pro)	DPH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
977786	NM_003482.4(KMT2D):c.12165del (p.Glu4056fs)	KMT2D	Pathogenic	criteria provided, single submitter
547521	NM_000381.4(MID1):c.829C>T (p.Arg277Ter)	MID1	Pathogenic	criteria provided, multiple submitters, no conflicts
375682	NM_002609.4(PDGFRB):c.1696T>C (p.Trp566Arg)	PDGFRB	Pathogenic	criteria provided, multiple submitters, no conflicts
632607	NM_006346.4(PIBF1):c.1918A>T (p.Ile640Phe)	PIBF1	Pathogenic/Likely pathogenic	no assertion criteria provided
254648	NM_002709.3(PPP1CB):c.146C>G (p.Pro49Arg)	PPP1CB	Pathogenic	reviewed by expert panel
632591	NM_014159.7(SETD2):c.4997A>G (p.Tyr1666Cys)	SETD2	Pathogenic/Likely pathogenic	no assertion criteria provided
427935	NM_001352754.2(ARMC9):c.1474G>A (p.Gly492Arg)	ARMC9	Likely pathogenic	criteria provided, single submitter
242888	NM_177433.3(MAGED2):c.1003del (p.Gln335fs)	MAGED2	Likely pathogenic	no assertion criteria provided
598934	NM_006346.4(PIBF1):c.1508A>G (p.Tyr503Cys)	PIBF1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
242889	NM_031442.4(TMEM47):c.35G>C (p.Arg12Pro)	TMEM47	Likely pathogenic	no assertion criteria provided
372561	NM_006009.4(TUBA1A):c.652G>A (p.Asp218Asn)	TUBA1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
632587	NM_020134.4(DPYSL5):c.139G>A (p.Gly47Arg)	DPYSL5	Uncertain significance	criteria provided, single submitter
3383292	NM_015859.4(GTF2A1):c.1030A>G (p.Arg344Gly)	GTF2A1	Uncertain significance	criteria provided, single submitter
632593	NM_031307.4(PUS3):c.578G>A (p.Arg193Gln)	HYLS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
632594	NM_031307.4(PUS3):c.497G>A (p.Arg166Gln)	HYLS1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 40 · 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
ZIC1	Limited	Autosomal dominant	Dandy-Walker syndrome	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZIC1	Orphanet:269212	Isolated Dandy-Walker malformation with hydrocephalus
ZIC1	Orphanet:269215	Isolated Dandy-Walker malformation without hydrocephalus
ZIC1	Orphanet:35099	Non-syndromic bicoronal craniosynostosis
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
MAGED2	Orphanet:570371	Bartter syndrome type 5
SETD2	Orphanet:597738	Luscan-Lumish syndrome
SETD2	Orphanet:597743	SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome
DPYSL5	Orphanet:528084	Non-specific syndromic intellectual disability
DPYSL5	Orphanet:7	3C syndrome
ARMC9	Orphanet:475	Isolated Joubert syndrome
TUBA1A	Orphanet:171680	Lissencephaly due to TUBA1A mutation
TUBA1A	Orphanet:45358	Congenital fibrosis of extraocular muscles
TUBA1A	Orphanet:467166	Tubulinopathy-associated dysgyria
TUBA1A	Orphanet:994	Fetal akinesia deformation sequence
PIBF1	Orphanet:475	Isolated Joubert syndrome
HYLS1	Orphanet:2189	Hydrolethalus
HYLS1	Orphanet:475	Isolated Joubert syndrome
BLTP1	Orphanet:610569	KIAA1109-related early lethal congenital brain malformations-arthrogryposis syndrome
DPH1	Orphanet:459061	Craniofacial dysplasia-short stature-ectodermal anomalies-intellectual disability syndrome
MID1	Orphanet:2745	Opitz GBBB syndrome
KMT2D	Orphanet:2322	Kabuki syndrome
KMT2D	Orphanet:589856	Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome
PDGFRB	Orphanet:168950	Myeloid/lymphoid neoplasm associated with PDGFRB rearrangement
PDGFRB	Orphanet:1980	Bilateral striopallidodentate calcinosis
PDGFRB	Orphanet:2591	Infantile myofibromatosis
PDGFRB	Orphanet:314950	Primary hypereosinophilic syndrome
PDGFRB	Orphanet:363665	Acroosteolysis-keloid-like lesions-premature aging syndrome
PDGFRB	Orphanet:477831	Kosaki overgrowth syndrome
PDGFRB	Orphanet:86830	Chronic myeloproliferative disease, unclassifiable
PPP1CB	Orphanet:2701	Noonan syndrome-like disorder with loose anagen hair

Cohort genes → proteins

17 cohort genes, 17 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	17

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ZIC1	HGNC:12872	ENSG00000152977	Q15915	Zinc finger protein ZIC 1	gencc
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	clinvar
MAGED2	HGNC:16353	ENSG00000102316	Q9UNF1	Melanoma-associated antigen D2	clinvar
SETD2	HGNC:18420	ENSG00000181555	Q9BYW2	Histone-lysine N-methyltransferase SETD2	clinvar
TMEM47	HGNC:18515	ENSG00000147027	Q9BQJ4	Transmembrane protein 47	clinvar
DPYSL5	HGNC:20637	ENSG00000157851	Q9BPU6	Dihydropyrimidinase-related protein 5	clinvar
ARMC9	HGNC:20730	ENSG00000135931	Q7Z3E5	LisH domain-containing protein ARMC9	clinvar
TUBA1A	HGNC:20766	ENSG00000167552	Q71U36	Tubulin alpha-1A chain	clinvar
PIBF1	HGNC:23352	ENSG00000083535	Q8WXW3	Progesterone-induced-blocking factor 1	clinvar
HYLS1	HGNC:26558	ENSG00000198331	Q96M11	Centriolar and ciliogenesis-associated protein HYLS1	clinvar
BLTP1	HGNC:26953	ENSG00000138688	Q2LD37	Bridge-like lipid transfer protein family member 1	clinvar
DPH1	HGNC:3003	ENSG00000108963	Q9BZG8	2-(3-amino-3-carboxypropyl)histidine synthase subunit 1	clinvar
GTF2A1	HGNC:4646	ENSG00000165417	P52655	Transcription initiation factor IIA subunit 1	clinvar
MID1	HGNC:7095	ENSG00000101871	O15344	E3 ubiquitin-protein ligase Midline-1	clinvar
KMT2D	HGNC:7133	ENSG00000167548	O14686	Histone-lysine N-methyltransferase 2D	clinvar
PDGFRB	HGNC:8804	ENSG00000113721	P09619	Platelet-derived growth factor receptor beta	clinvar
PPP1CB	HGNC:9282	ENSG00000213639	P62140	Serine/threonine-protein phosphatase PP1-beta catalytic subunit	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZIC1	Zinc finger protein ZIC 1	Acts as a transcriptional activator.
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
MAGED2	Melanoma-associated antigen D2	Regulates the expression, localization to the plasma membrane and function of the sodium chloride cotransporters SLC12A1 and SLC12A3, two key components of salt reabsorption in the distal renal tubule.
SETD2	Histone-lysine N-methyltransferase SETD2	Histone methyltransferase that specifically trimethylates ‘Lys-36’ of histone H3 (H3K36me3) using dimethylated ‘Lys-36’ (H3K36me2) as substrate.
TMEM47	Transmembrane protein 47	Regulates cell junction organization in epithelial cells.
DPYSL5	Dihydropyrimidinase-related protein 5	Involved in the negative regulation of dendrite outgrowth.
ARMC9	LisH domain-containing protein ARMC9	Involved in ciliogenesis.
TUBA1A	Tubulin alpha-1A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
PIBF1	Progesterone-induced-blocking factor 1	Plays a role in ciliogenesis.
HYLS1	Centriolar and ciliogenesis-associated protein HYLS1	Plays a role in ciliogenesis.
BLTP1	Bridge-like lipid transfer protein family member 1	Bridge-like lipid transfer protein that functions as molecular bridges between endoplasmic reticulum and the membranes targeted for lipid delivery.
DPH1	2-(3-amino-3-carboxypropyl)histidine synthase subunit 1	Catalyzes the first step of diphthamide biosynthesis, a post-translational modification of histidine which occurs in elongation factor 2.
GTF2A1	Transcription initiation factor IIA subunit 1	TFIIA is a component of the transcription machinery of RNA polymerase II and plays an important role in transcriptional activation.
MID1	E3 ubiquitin-protein ligase Midline-1	Has E3 ubiquitin ligase activity towards IGBP1, promoting its monoubiquitination, which results in deprotection of the catalytic subunit of protein phosphatase PP2A, and its subsequent degradation by polyubiquitination.
KMT2D	Histone-lysine N-methyltransferase 2D	Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4).
PDGFRB	Platelet-derived growth factor receptor beta	Tyrosine-protein kinase that acts as a cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, surviv…
PPP1CB	Serine/threonine-protein phosphatase PP1-beta catalytic subunit	Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets.

Protein-family classification

Druggable: 3 · Difficult: 5 · Unknown: 9 · Druggable fraction: 0.18

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
Phosphatase	1	4.9×	0.307
Kinase	2	3.3×	0.307
Transcription factor	4	1.9×	0.307
Scaffold/PPI	1	1.0×	0.687
Other/Unknown	9	0.9×	0.687

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZIC1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Znf_ZIC
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
MAGED2	Other/Unknown	no		MHD_dom, MAGE, MAGE_WH1
SETD2	Scaffold/PPI	no	2.1.1.359	WW_dom, SET_dom, Post-SET_dom
TMEM47	Transcription factor	no		PMP22/EMP/MP20/Claudin, P53_induced
DPYSL5	Other/Unknown	no		Amidohydro-rel, Metal-dep_hydrolase_composite, Hydantoinase/dihydroPyrase
ARMC9	Other/Unknown	no		LisH, ARM-like, ARM-type_fold
TUBA1A	Other/Unknown	no		Tubulin, Alpha_tubulin, Tubulin_FtsZ_GTPase
PIBF1	Other/Unknown	no		PIBF1
HYLS1	Other/Unknown	no		HYLS1, HYLS1_C_dom, Centriolar_ciliogenesis_assoc
BLTP1	Other/Unknown	no		BLTP1, BLTP1_N, BLTP1_M
DPH1	Other/Unknown	no		DPH1/DPH2, DPH1/DPH2_1, DPH1/DPH2_2
GTF2A1	Other/Unknown	no		TFIIA_asu/bsu, TFIIA_b-brl
MID1	Transcription factor	no		Znf_B-box, Znf_RING, B30.2/SPRY
KMT2D	Transcription factor	no		SET_dom, Znf_RING, Znf_PHD
PDGFRB	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
PPP1CB	Phosphatase	yes	3.1.3.16	Calcineurin-like_PHP, Ser/Thr-sp_prot-phosphatase, Metallo-depent_PP-like

Expression context

Cohort genes with no expression data: 0.

16 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)	17
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	3
calcaneal tendon	3
ventricular zone	3
colonic epithelium	2
adenohypophysis	2
endothelial cell	2
cortical plate	2
ganglionic eminence	2
oocyte	2
secondary oocyte	2
stromal cell of endometrium	2
sural nerve	2
cerebellum	1
cranial nerve II	1
paraflocculus	1
left ovary	1
right ovary	1
tendon of biceps brachii	1
choroid plexus epithelium	1
saphenous vein	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZIC1	196	broad	marker	paraflocculus, cranial nerve II, cerebellum
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
MAGED2	291	ubiquitous	marker	left ovary, adenohypophysis, right ovary
SETD2	291	ubiquitous	marker	tendon of biceps brachii, endothelial cell, colonic epithelium
TMEM47	288	ubiquitous	marker	choroid plexus epithelium, saphenous vein, urethra
DPYSL5	133	broad	marker	cortical plate, ganglionic eminence, ventricular zone
ARMC9	244	ubiquitous	marker	stromal cell of endometrium, secondary oocyte, oocyte
TUBA1A	288	ubiquitous	marker	endothelial cell, cortical plate, ganglionic eminence
PIBF1	273	ubiquitous	marker	calcaneal tendon, ventricular zone, sural nerve
HYLS1	205	ubiquitous	yes	oocyte, secondary oocyte, sperm
BLTP1	298	ubiquitous	marker	Brodmann (1909) area 23, corpus callosum, postcentral gyrus
DPH1	140	ubiquitous	marker	pituitary gland, right hemisphere of cerebellum, adenohypophysis
GTF2A1	271	ubiquitous	marker	esophagus squamous epithelium, tibia, corpus epididymis
MID1	283	ubiquitous	marker	mucosa of paranasal sinus, ventricular zone, cervix squamous epithelium
KMT2D	272	ubiquitous	marker	buccal mucosa cell, medial globus pallidus, sural nerve
PDGFRB	270	ubiquitous	marker	stromal cell of endometrium, right coronary artery, endocervix
PPP1CB	295	ubiquitous	marker	calcaneal tendon, amniotic fluid, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRAF	7,394
PDGFRB	5,111
SETD2	4,668
KMT2D	3,223
ZIC1	2,710
PIBF1	1,706
DPYSL5	1,690
GTF2A1	1,621
DPH1	1,593
TUBA1A	1,436

Structural data

PDB: 8 · AlphaFold-only: 9 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRAF	P15056	131
GTF2A1	P52655	52
SETD2	Q9BYW2	43
TUBA1A	Q71U36	15
KMT2D	O14686	11
PDGFRB	P09619	8
MID1	O15344	5
DPYSL5	Q9BPU6	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PPP1CB	P62140	91.91
DPH1	Q9BZG8	87.00
TMEM47	Q9BQJ4	86.19
PIBF1	Q8WXW3	77.70
ARMC9	Q7Z3E5	71.71
HYLS1	Q96M11	66.11
MAGED2	Q9UNF1	59.89
ZIC1	Q15915	55.77
BLTP1	Q2LD37

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 188. Enrichment computed across 17 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
SHOC2 M1731 mutant abolishes MRAS complex function	2	237.9×	0.003	BRAF, PPP1CB
Gain-of-function MRAS complexes activate RAF signaling	2	237.9×	0.003	BRAF, PPP1CB
RAF activation	2	56.0×	0.035	BRAF, PPP1CB
PKMTs methylate histone lysines	2	26.8×	0.114	SETD2, KMT2D
Signaling by MRAS-complex mutants	1	237.9×	0.117	BRAF
Signalling to p38 via RIT and RIN	1	190.3×	0.117	BRAF
Loss of Function of KMT2D in MLL4 Complex Formation in Kabuki Syndrome	1	190.3×	0.117	KMT2D
Negative feedback regulation of MAPK pathway	1	158.6×	0.117	BRAF
ARMS-mediated activation	1	135.9×	0.117	BRAF
Prolonged ERK activation events	1	119.0×	0.117	BRAF
Synthesis of diphthamide-EEF2	1	119.0×	0.117	DPH1
Signaling by FGFR3	1	95.2×	0.117	BRAF
Signaling by FGFR4	1	86.5×	0.117	BRAF
Frs2-mediated activation	1	79.3×	0.117	BRAF
Signaling by FGFR1	1	68.0×	0.117	BRAF
Phosphorylation and nuclear translocation of the CRY:PER:kinase complex	1	68.0×	0.117	PPP1CB
Maturation of hRSV A proteins	1	63.4×	0.117	PPP1CB
Spry regulation of FGF signaling	1	59.5×	0.117	BRAF
CRMPs in Sema3A signaling	1	52.9×	0.117	DPYSL5
Specification of the neural plate border	1	52.9×	0.117	ZIC1
Signalling to ERKs	1	50.1×	0.117	BRAF
RHO GTPases activate CIT	1	50.1×	0.117	PPP1CB
RHO GTPases Activate ROCKs	1	50.1×	0.117	PPP1CB
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	45.3×	0.117	TUBA1A
Transport of connexons to the plasma membrane	1	45.3×	0.117	TUBA1A
RHO GTPases activate PAKs	1	45.3×	0.117	PPP1CB
Gap junction trafficking and regulation	1	39.6×	0.117	TUBA1A
Triglyceride catabolism	1	39.6×	0.117	PPP1CB
Gap junction trafficking	1	39.6×	0.117	TUBA1A
Post-chaperonin tubulin folding pathway	1	39.6×	0.117	TUBA1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 17 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cell migration involved in coronary angiogenesis	1	991.3×	0.035	PDGFRB
metanephric glomerular mesangial cell proliferation involved in metanephros development	1	991.3×	0.035	PDGFRB
beta-catenin-TCF complex assembly	1	991.3×	0.035	KMT2D
negative regulation of prostaglandin biosynthetic process	1	495.6×	0.035	PIBF1
cell migration involved in vasculogenesis	1	495.6×	0.035	PDGFRB
smooth muscle cell chemotaxis	1	495.6×	0.035	PDGFRB
maintenance of cell number	1	495.6×	0.035	ZIC1
positive regulation of metanephric mesenchymal cell migration by platelet-derived growth factor receptor-beta signaling pathway	1	330.4×	0.035	PDGFRB
positive regulation of cell proliferation by VEGF-activated platelet derived growth factor receptor signaling pathway	1	330.4×	0.035	PDGFRB
negative regulation of tyrosine phosphorylation of STAT protein	1	330.4×	0.035	PIBF1
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	330.4×	0.035	BRAF
metanephric glomerular capillary formation	1	330.4×	0.035	PDGFRB
regulation of protein localization to chromatin	1	330.4×	0.035	SETD2
pattern specification process	2	55.1×	0.035	ZIC1, MID1
visual learning	2	36.0×	0.035	BRAF, TUBA1A
cellular response to calcium ion	2	23.6×	0.035	BRAF, TUBA1A
cilium assembly	3	13.0×	0.035	ARMC9, PIBF1, HYLS1
oocyte growth	1	247.8×	0.036	KMT2D
smooth muscle adaptation	1	247.8×	0.036	PDGFRB
activation of Janus kinase activity	1	247.8×	0.036	PIBF1
microtubule cytoskeleton organization involved in mitosis	1	247.8×	0.036	SETD2
pyramidal neuron differentiation	1	198.3×	0.038	TUBA1A
platelet-derived growth factor receptor-beta signaling pathway	1	198.3×	0.038	PDGFRB
positive regulation of axon regeneration	1	198.3×	0.038	BRAF
negative regulation of synaptic vesicle exocytosis	1	198.3×	0.038	BRAF
peptidyl-lysine trimethylation	1	165.2×	0.038	SETD2
cerebellar cortex morphogenesis	1	165.2×	0.038	TUBA1A
nucleosome organization	1	165.2×	0.038	SETD2
CD4-positive, alpha-beta T cell differentiation	1	165.2×	0.038	BRAF
MAPK cascade	2	18.0×	0.038	BRAF, PPP1CB

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 13

Druggability breadth: 7 of 17 evidence-associated genes (41%) 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
BRAF	VEMURAFENIB
TUBA1A	COLCHICINE
PDGFRB	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDGFRB	102	4
BRAF	48	4
TUBA1A	22	4
SETD2	3	2
ZIC1	0	0
MAGED2	0	0
TMEM47	0	0
DPYSL5	0	0
ARMC9	0	0
PIBF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF, PDGFRB
FEDRATINIB	4	BRAF, PDGFRB
SORAFENIB	4	BRAF, PDGFRB
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF, PDGFRB
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF, PDGFRB
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF, PDGFRB
PAZOPANIB	4	BRAF, PDGFRB
DASATINIB	4	BRAF, PDGFRB
ERLOTINIB	4	BRAF, PDGFRB
GEFITINIB	4	BRAF
IMATINIB	4	BRAF, PDGFRB
COLCHICINE	4	TUBA1A
VINBLASTINE	4	TUBA1A
LEVOFLOXACIN ANHYDROUS	4	TUBA1A
DOCETAXEL	4	TUBA1A
NOSCAPINE	4	TUBA1A
VINBLASTINE SULFATE	4	TUBA1A
PACLITAXEL	4	TUBA1A
LEVOFLOXACIN	4	TUBA1A
VINORELBINE	4	TUBA1A
TIRBANIBULIN	4	TUBA1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
TUBA1A	1,696	Binding:1655, Functional:35, ADMET:6
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
PDGFRB	1,237	Binding:1213, Functional:16, ADMET:8
SETD2	64	Binding:64
KMT2D	11	Binding:11
PPP1CB	9	Binding:9
GTF2A1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
SETD2	2.1.1.359	[histone H3]-lysine36 N-trimethyltransferase
PDGFRB	2.7.10.1	receptor protein-tyrosine kinase
PPP1CB	3.1.3.16	protein-serine/threonine phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BRAF	1,442
TUBA1A	1,696
PDGFRB	1,237

Pharmacogenomics

Cohort genes with a PharmGKB record: 17; 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)
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF, PDGFRB
FEDRATINIB	4	BRAF, PDGFRB
SORAFENIB	4	BRAF, PDGFRB
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF, PDGFRB
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF, PDGFRB
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF, PDGFRB
PAZOPANIB	4	BRAF, PDGFRB
DASATINIB	4	BRAF, PDGFRB
ERLOTINIB	4	BRAF, PDGFRB
GEFITINIB	4	BRAF
IMATINIB	4	BRAF, PDGFRB
COLCHICINE	4	TUBA1A
VINBLASTINE	4	TUBA1A
LEVOFLOXACIN ANHYDROUS	4	TUBA1A
DOCETAXEL	4	TUBA1A
NOSCAPINE	4	TUBA1A
VINBLASTINE SULFATE	4	TUBA1A
PACLITAXEL	4	TUBA1A
LEVOFLOXACIN	4	TUBA1A
VINORELBINE	4	TUBA1A
TIRBANIBULIN	4	TUBA1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	BRAF, TUBA1A, PDGFRB
B	Phased (≥1) drug, not yet approved	1	SETD2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PPP1CB
E	Difficult family or no structure, no drug	12	ZIC1, MAGED2, TMEM47, DPYSL5, ARMC9, PIBF1, HYLS1, BLTP1, DPH1, GTF2A1 (+2 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZIC1	0	—
MAGED2	0	—
TMEM47	0	—
DPYSL5	0	—
ARMC9	0	—
PIBF1	0	—
HYLS1	0	—
BLTP1	0	—
DPH1	0	—
GTF2A1	2	—
MID1	0	—
KMT2D	11	—
PPP1CB	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.