Noonan syndrome 8

Summary

Noonan syndrome 8 (MONDO:0014143) is a disease caused by RIT1 (GenCC Definitive), with 6 cohort genes.

At a glance

• Causal gene: RIT1 (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 307

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Noonan syndrome 8
Mondo ID	MONDO:0014143
OMIM	615355
DOID	DOID:0060586
NCIT	C176936
UMLS	C3809233
MedGen	815563
GARD	0015949
Is cancer (heuristic)	no

Also known as: Noonan syndrome 8 · Noonan syndrome caused by mutation in RIT1 · Noonan syndrome type 8 · NS8 · RIT1 Noonan syndrome

Data availability: 307 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Noonan syndrome › Noonan syndrome 8

Related subtypes (13): Noonan syndrome 1, Noonan syndrome 2, Noonan syndrome 3, Noonan syndrome 4, Noonan syndrome 5, Noonan syndrome 6, Noonan syndrome 7, Noonan syndrome 9, Noonan syndrome 10, Noonan syndrome 14, Noonan syndrome 11, noonan syndrome 12, Noonan syndrome 13

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

307 retrieved; paginated sample, class counts are floors:

136 uncertain significance, 108 likely benign, 20 conflicting classifications of pathogenicity, 17 pathogenic, 15 pathogenic/likely pathogenic, 4 benign, 4 likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2425657	NC_000001.10:g.(?155581953)(155880552_?)del	DAP3	Pathogenic	criteria provided, single submitter
376489	NM_006218.4(PIK3CA):c.1034A>C (p.Asn345Thr)	PIK3CA	Pathogenic	criteria provided, single submitter
120250	NM_006912.6(RIT1):c.270G>A (p.Met90Ile)	RIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1695891	NM_006912.6(RIT1):c.67A>G (p.Lys23Glu)	RIT1	Pathogenic	criteria provided, single submitter
181522	NM_006912.6(RIT1):c.246T>G (p.Phe82Leu)	RIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183401	NM_006912.6(RIT1):c.104G>C (p.Ser35Thr)	RIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
183403	NM_006912.6(RIT1):c.229G>A (p.Ala77Thr)	RIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183404	NM_006912.6(RIT1):c.241G>C (p.Glu81Gln)	RIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183405	NM_006912.6(RIT1):c.242A>G (p.Glu81Gly)	RIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183406	NM_006912.6(RIT1):c.244T>A (p.Phe82Ile)	RIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
183407	NM_006912.6(RIT1):c.244T>C (p.Phe82Leu)	RIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
183408	NM_006912.6(RIT1):c.244T>G (p.Phe82Val)	RIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
183409	NM_006912.6(RIT1):c.247A>C (p.Thr83Pro)	RIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
183410	NM_006912.6(RIT1):c.251C>T (p.Ala84Val)	RIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183411	NM_006912.6(RIT1):c.265T>C (p.Tyr89His)	RIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
190305	NM_006912.6(RIT1):c.270G>C (p.Met90Ile)	RIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224122	NM_006912.6(RIT1):c.67A>C (p.Lys23Gln)	RIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
228289	NM_006912.6(RIT1):c.229G>C (p.Ala77Pro)	RIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2431215	NM_006912.6(RIT1):c.111G>C (p.Met37Ile)	RIT1	Pathogenic	criteria provided, single submitter
265328	NM_006912.6(RIT1):c.270G>T (p.Met90Ile)	RIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
280151	NM_006912.6(RIT1):c.259G>C (p.Asp87His)	RIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280609	NM_006912.6(RIT1):c.365G>T (p.Arg122Leu)	RIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382471	NM_006912.6(RIT1):c.269T>C (p.Met90Thr)	RIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370035	NM_006912.6(RIT1):c.246T>A (p.Phe82Leu)	RIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
372863	NM_006912.6(RIT1):c.245T>G (p.Phe82Cys)	RIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
561621	NM_006912.6(RIT1):c.229G>T (p.Ala77Ser)	RIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
561681	NM_006912.6(RIT1):c.268A>G (p.Met90Val)	RIT1	Pathogenic	reviewed by expert panel
581105	NM_006912.6(RIT1):c.69A>C (p.Lys23Asn)	RIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
60506	NM_006912.6(RIT1):c.170C>G (p.Ala57Gly)	RIT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60509	NM_006912.6(RIT1):c.284G>C (p.Gly95Ala)	RIT1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 16 · 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
RIT1	Definitive	Autosomal dominant	Noonan syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RIT1	Orphanet:648	Noonan syndrome
PIK3CA	Orphanet:140944	CLOVES syndrome
PIK3CA	Orphanet:144	Lynch syndrome
PIK3CA	Orphanet:168984	CLAPO syndrome
PIK3CA	Orphanet:201	Cowden syndrome
PIK3CA	Orphanet:210159	Adult hepatocellular carcinoma
PIK3CA	Orphanet:221061	Familial cerebral cavernous malformation
PIK3CA	Orphanet:2495	Meningioma
PIK3CA	Orphanet:276280	Hemihyperplasia-multiple lipomatosis syndrome
PIK3CA	Orphanet:295239	Macrodactyly of fingers, unilateral
PIK3CA	Orphanet:295243	Macrodactyly of toes, unilateral
PIK3CA	Orphanet:314662	Segmental progressive overgrowth syndrome with fibroadipose hyperplasia
PIK3CA	Orphanet:60040	Megalencephaly-capillary malformation-polymicrogyria syndrome
PIK3CA	Orphanet:714737	Diffuse capillary malformation with overgrowth
PIK3CA	Orphanet:90308	Capillary-lymphatic-venous malformation with segmental distribution
PIK3CA	Orphanet:99802	Hemimegalencephaly

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RIT1	HGNC:10023	ENSG00000143622	Q92963	GTP-binding protein Rit1	gencc,clinvar
DAP3	HGNC:2673	ENSG00000132676	P51398	Small ribosomal subunit protein mS29	clinvar
DLGAP3	HGNC:30368	ENSG00000116544	O95886	Disks large-associated protein 3	clinvar
HSH2D-AS1	HGNC:58332	ENSG00000269243		HSH2D and RAB8A antisense RNA 1	clinvar
ARHGEF2	HGNC:682	ENSG00000116584	Q92974	Rho guanine nucleotide exchange factor 2	clinvar
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RIT1	GTP-binding protein Rit1	Plays a crucial role in coupling NGF stimulation to the activation of both EPHB2 and MAPK14 signaling pathways and in NGF-dependent neuronal differentiation.
DAP3	Small ribosomal subunit protein mS29	As a component of the mitochondrial small ribosomal subunit, it plays a role in the translation of mitochondrial mRNAs.
DLGAP3	Disks large-associated protein 3	May play a role in the molecular organization of synapses and neuronal cell signaling.
ARHGEF2	Rho guanine nucleotide exchange factor 2	Activates Rho-GTPases by promoting the exchange of GDP for GTP.
PIK3CA	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.17

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	4.6×	0.451
Scaffold/PPI	1	2.9×	0.451
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RIT1	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
DAP3	Other/Unknown	no		Ribosomal_mS29_met, Ribosomal_mS29, P-loop_NTPase
DLGAP3	Other/Unknown	no		SAPAP
HSH2D-AS1	Other/Unknown	no
ARHGEF2	Scaffold/PPI	no		DH_dom, PH_domain, PKC_DAG/PE
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom

Expression context

Cohort genes with no expression data: 0.

4 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	2
leukocyte	1
monocyte	1
mononuclear cell	1
body of pancreas	1
colonic epithelium	1
anterior cingulate cortex	1
nucleus accumbens	1
right frontal lobe	1
bone marrow cell	1
granulocyte	1
mucosa of transverse colon	1
corpus callosum	1
ganglionic eminence	1
inferior vagus X ganglion	1
calcaneal tendon	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RIT1	268	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
DAP3	294	ubiquitous	marker	body of pancreas, adrenal tissue, colonic epithelium
DLGAP3	150	broad	yes	right frontal lobe, anterior cingulate cortex, nucleus accumbens
HSH2D-AS1	133		yes	mucosa of transverse colon, granulocyte, bone marrow cell
ARHGEF2	297	ubiquitous	marker	inferior vagus X ganglion, ganglionic eminence, corpus callosum
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIK3CA	5,157
DAP3	3,504
RIT1	3,298
ARHGEF2	2,202
DLGAP3	1,613
HSH2D-AS1	0

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3CA	P42336	135
DAP3	P51398	77
ARHGEF2	Q92974	60
RIT1	Q92963	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DLGAP3	O95886	50.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 82. Enrichment computed across 6 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signalling to p38 via RIT and RIN	1	456.8×	0.026	RIT1
MET activates PI3K/AKT signaling	1	380.7×	0.026	PIK3CA
Activated NTRK3 signals through PI3K	1	380.7×	0.026	PIK3CA
Activated NTRK2 signals through PI3K	1	326.3×	0.026	PIK3CA
Signaling by LTK in cancer	1	326.3×	0.026	PIK3CA
PI3K/AKT activation	1	253.8×	0.026	PIK3CA
IRS-mediated signalling	1	207.6×	0.026	PIK3CA
PI3K events in ERBB4 signaling	1	207.6×	0.026	PIK3CA
Co-stimulation by ICOS	1	207.6×	0.026	PIK3CA
Signaling by FGFR4 in disease	1	190.3×	0.026	PIK3CA
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	190.3×	0.026	PIK3CA
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	175.7×	0.026	PIK3CA
Signaling by PDGFRA extracellular domain mutants	1	175.7×	0.026	PIK3CA
Signaling by LTK	1	175.7×	0.026	PIK3CA
Signaling by FLT3 ITD and TKD mutants	1	152.3×	0.026	PIK3CA
Constitutive Signaling by EGFRvIII	1	142.8×	0.026	PIK3CA
PI3K events in ERBB2 signaling	1	134.3×	0.026	PIK3CA
Signaling by ERBB2 ECD mutants	1	134.3×	0.026	PIK3CA
GAB1 signalosome	1	126.9×	0.026	PIK3CA
Signaling by cytosolic FGFR1 fusion mutants	1	126.9×	0.026	PIK3CA
PI-3K cascade:FGFR3	1	126.9×	0.026	PIK3CA
Tie2 Signaling	1	120.2×	0.026	PIK3CA
Role of LAT2/NTAL/LAB on calcium mobilization	1	120.2×	0.026	PIK3CA
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	1	114.2×	0.026	PIK3CA
Signaling by ALK	1	114.2×	0.026	PIK3CA
PI-3K cascade:FGFR4	1	114.2×	0.026	PIK3CA
Signaling by FLT3 fusion proteins	1	114.2×	0.026	PIK3CA
PI-3K cascade:FGFR1	1	103.8×	0.026	PIK3CA
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	103.8×	0.026	PIK3CA
PI-3K cascade:FGFR2	1	99.3×	0.026	PIK3CA

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
response to muscle inactivity	1	3370.4×	0.012	PIK3CA
response to butyrate	1	3370.4×	0.012	PIK3CA
response to L-leucine	1	1123.5×	0.014	PIK3CA
asymmetric neuroblast division	1	1123.5×	0.014	ARHGEF2
cellular response to hydrostatic pressure	1	1123.5×	0.014	PIK3CA
negative regulation of intrinsic apoptotic signaling pathway in response to osmotic stress	1	842.6×	0.015	ARHGEF2
negative regulation of actin filament depolymerization	1	561.7×	0.015	PIK3CA
regulation of cellular respiration	1	561.7×	0.015	PIK3CA
regulation of actin filament organization	1	481.5×	0.015	PIK3CA
autosome genomic imprinting	1	481.5×	0.015	PIK3CA
negative regulation of fibroblast apoptotic process	1	481.5×	0.015	PIK3CA
modification of postsynaptic structure	1	374.5×	0.015	DLGAP3
cellular response to muramyl dipeptide	1	337.0×	0.015	ARHGEF2
cardiac muscle cell contraction	1	337.0×	0.015	PIK3CA
positive regulation of protein localization to membrane	1	337.0×	0.015	PIK3CA
signaling	1	306.4×	0.015	DLGAP3
TORC2 signaling	1	306.4×	0.015	PIK3CA
phosphatidylinositol-3-phosphate biosynthetic process	1	259.3×	0.015	PIK3CA
anoikis	1	259.3×	0.015	PIK3CA
relaxation of cardiac muscle	1	259.3×	0.015	PIK3CA
cellular hyperosmotic response	1	240.7×	0.015	ARHGEF2
response to dexamethasone	1	240.7×	0.015	PIK3CA
vasculature development	1	224.7×	0.015	PIK3CA
negative regulation of macroautophagy	1	224.7×	0.015	PIK3CA
vascular endothelial growth factor signaling pathway	1	210.7×	0.015	PIK3CA
negative regulation of necroptotic process	1	198.3×	0.015	ARHGEF2
positive regulation of neuron migration	1	198.3×	0.015	ARHGEF2
apoptotic mitochondrial changes	1	177.4×	0.015	DAP3
negative regulation of anoikis	1	177.4×	0.015	PIK3CA
positive regulation of peptidyl-tyrosine phosphorylation	1	160.5×	0.016	ARHGEF2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 6 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PIK3CA	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3CA	67	4
ARHGEF2	1	2
RIT1	0	0
DAP3	0	0
DLGAP3	0	0
HSH2D-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDELALISIB	4	PIK3CA
ALPELISIB	4	PIK3CA
DUVELISIB	4	PIK3CA
COPANLISIB	4	PIK3CA
FEDRATINIB	4	PIK3CA
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	PIK3CA
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	PIK3CA
TASELISIB	3	PIK3CA
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	PIK3CA
MOLIBRESIB	2	ARHGEF2
OMIPALISIB	2	PIK3CA
VISTUSERTIB	2	PIK3CA
FIMEPINOSTAT	2	PIK3CA
EGANELISIB	2	PIK3CA
BERZOSERTIB	2	PIK3CA
BIMIRALISIB	2	PIK3CA
PICTILISIB	2	PIK3CA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PIK3CA	2,034	Binding:2009, ADMET:19, Toxicity:4, Functional:2
ARHGEF2	8	Binding:8
DAP3	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PIK3CA	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PIK3CA	2,034

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

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)
IDELALISIB	4	PIK3CA
ALPELISIB	4	PIK3CA
DUVELISIB	4	PIK3CA
COPANLISIB	4	PIK3CA
FEDRATINIB	4	PIK3CA
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	PIK3CA
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	PIK3CA
TASELISIB	3	PIK3CA
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	PIK3CA
MOLIBRESIB	2	ARHGEF2
OMIPALISIB	2	PIK3CA
VISTUSERTIB	2	PIK3CA
FIMEPINOSTAT	2	PIK3CA
EGANELISIB	2	PIK3CA
BERZOSERTIB	2	PIK3CA
BIMIRALISIB	2	PIK3CA
PICTILISIB	2	PIK3CA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PIK3CA
B	Phased (≥1) drug, not yet approved	1	ARHGEF2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	RIT1, DAP3, DLGAP3, HSH2D-AS1

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)
RIT1	0	—
DAP3	2	—
DLGAP3	0	—
HSH2D-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.