Megalencephaly-capillary malformation-polymicrogyria syndrome

Summary

Megalencephaly-capillary malformation-polymicrogyria syndrome (MONDO:0011240) is a disease caused by PIK3CA (GenCC Strong), with 4 cohort genes and 1 clinical trial. The dominant Reactome pathway is CD28 dependent PI3K/Akt signaling (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PIK3CA (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 62
• Phenotypes (HPO): 35
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		170	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0000154	Wide mouth	Very frequent (80-99%)
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000324	Facial asymmetry	Very frequent (80-99%)
HP:0001052	Nevus flammeus	Very frequent (80-99%)
HP:0001161	Hand polydactyly	Very frequent (80-99%)
HP:0001770	Toe syndactyly	Very frequent (80-99%)
HP:0001829	Foot polydactyly	Very frequent (80-99%)
HP:0006101	Finger syndactyly	Very frequent (80-99%)
HP:0100026	Arteriovenous malformation	Very frequent (80-99%)
HP:0100555	Asymmetric growth	Very frequent (80-99%)
HP:0100585	Telangiectasia of the skin	Very frequent (80-99%)
HP:0100761	Visceral angiomatosis	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0000238	Hydrocephalus	Frequent (30-79%)
HP:0000293	Full cheeks	Frequent (30-79%)
HP:0000348	High forehead	Frequent (30-79%)
HP:0000965	Cutis marmorata	Frequent (30-79%)
HP:0001034	Hypermelanotic macule	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0007360	Aplasia/Hypoplasia of the cerebellum	Frequent (30-79%)
HP:0012639	Abnormal nervous system morphology	Frequent (30-79%)
HP:0000490	Deeply set eye	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0002126	Polymicrogyria	Occasional (5-29%)
HP:0002308	Chiari malformation	Occasional (5-29%)
HP:0002637	Cerebral ischemia	Occasional (5-29%)
HP:0002664	Neoplasm	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	megalencephaly-capillary malformation-polymicrogyria syndrome
Mondo ID	MONDO:0011240
MeSH	C536142
OMIM	602501
Orphanet	60040
SNOMED CT	703370002
UMLS	C1865285
MedGen	355421
GARD	0006950
NORD	1423
Is cancer (heuristic)	no

Also known as: M-CM · M-CMTC · macrocephaly cutis marmorata telangiectatica congenita · macrocephaly-capillary malformation syndrome · macrocephaly-cutis marmorata telangiectatica congenita syndrome · MCAP · MCM · MCMTC · megalencephaly cutis marmorata telangiectatica congenita · Megalencephaly-Capillary Malformation · megalencephaly-capillary malformation syndrome · megalencephaly-capillary malformation-polymicrogyria syndrome · megalencephaly-capillary malformation-polymicrogyria syndrome, somatic · megalencephaly-cutis marmorata telangiectatica congenita syndrome · megalocephaly cutis marmorata telangiectatica congenita

Data availability: 62 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes › megalencephaly-capillary malformation-polymicrogyria syndrome

Related subtypes (4): macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, isolated focal cortical dysplasia, megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome, hemimegalencephaly

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

62 retrieved; paginated sample, class counts are floors:

22 pathogenic, 20 uncertain significance, 12 pathogenic/likely pathogenic, 7 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
39815	NM_005465.7(AKT3):c.686A>G (p.Asn229Ser)	AKT3	Pathogenic	criteria provided, single submitter
1098323	NM_006218.4(PIK3CA):c.2816A>G (p.Asp939Gly)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172582	NM_006218.4(PIK3CA):c.344G>C (p.Arg115Pro)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172583	NM_006218.4(PIK3CA):c.3104C>T (p.Ala1035Val)	PIK3CA	Pathogenic	criteria provided, single submitter
1198826	NM_006218.4(PIK3CA):c.277C>T (p.Arg93Trp)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333250	NM_006218.4(PIK3CA):c.1345C>A (p.Pro449Thr)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13652	NM_006218.4(PIK3CA):c.3140A>G (p.His1047Arg)	PIK3CA	Pathogenic	reviewed by expert panel
13653	NM_006218.4(PIK3CA):c.3140A>T (p.His1047Leu)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
13655	NM_006218.4(PIK3CA):c.1633G>A (p.Glu545Lys)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13657	NM_006218.4(PIK3CA):c.1636C>A (p.Gln546Lys)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
179173	NM_006218.4(PIK3CA):c.3129G>A (p.Met1043Ile)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804026	NM_006218.4(PIK3CA):c.1346C>T (p.Pro449Leu)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217293	NM_006218.4(PIK3CA):c.1635G>T (p.Glu545Asp)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
218236	NM_006218.4(PIK3CA):c.335T>A (p.Ile112Asn)	PIK3CA	Pathogenic	no assertion criteria provided
280875	NM_006218.4(PIK3CA):c.323G>A (p.Arg108His)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31944	NM_006218.4(PIK3CA):c.1624G>A (p.Glu542Lys)	PIK3CA	Pathogenic	reviewed by expert panel
376049	NM_006218.4(PIK3CA):c.263G>A (p.Arg88Gln)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
376050	NM_006218.4(PIK3CA):c.1035T>A (p.Asn345Lys)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
376247	NM_006218.4(PIK3CA):c.3145G>A (p.Gly1049Ser)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
376470	NM_006218.4(PIK3CA):c.1357G>A (p.Glu453Lys)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
376476	NM_006218.4(PIK3CA):c.2176G>A (p.Glu726Lys)	PIK3CA	Pathogenic	reviewed by expert panel
376478	NM_006218.4(PIK3CA):c.241G>A (p.Glu81Lys)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
376489	NM_006218.4(PIK3CA):c.1034A>C (p.Asn345Thr)	PIK3CA	Pathogenic	criteria provided, single submitter
39703	NM_006218.4(PIK3CA):c.2740G>A (p.Gly914Arg)	PIK3CA	Pathogenic	reviewed by expert panel
39704	NM_006218.4(PIK3CA):c.1133G>A (p.Cys378Tyr)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
39705	NM_006218.4(PIK3CA):c.3139C>T (p.His1047Tyr)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
39706	NM_006218.4(PIK3CA):c.1356AGA[1] (p.Glu453del)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
418658	NM_006218.4(PIK3CA):c.1048G>A (p.Asp350Asn)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
419222	NM_006218.4(PIK3CA):c.1093G>A (p.Glu365Lys)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
809567	NM_006218.4(PIK3CA):c.1090G>A (p.Gly364Arg)	PIK3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 19 · 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
PIK3CA	Strong	Autosomal dominant	megalencephaly-capillary malformation-polymicrogyria syndrome	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
RIT1	Orphanet:648	Noonan syndrome
AKT3	Orphanet:83473	Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome
AKT3	Orphanet:99802	Hemimegalencephaly
PIK3R2	Orphanet:83473	Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	gencc,clinvar
RIT1	HGNC:10023	ENSG00000143622	Q92963	GTP-binding protein Rit1	clinvar
AKT3	HGNC:393	ENSG00000117020	Q9Y243	RAC-gamma serine/threonine-protein kinase	clinvar
PIK3R2	HGNC:8980	ENSG00000105647	O00459	Phosphatidylinositol 3-kinase regulatory subunit beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.
AKT3	RAC-gamma serine/threonine-protein kinase	AKT3 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis.
PIK3R2	Phosphatidylinositol 3-kinase regulatory subunit beta	Regulatory subunit of phosphoinositide-3-kinase (PI3K), a kinase that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3).

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.75

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	3	20.8×	4e-04
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom
RIT1	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
AKT3	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, PH_domain
PIK3R2	Kinase	yes	2.7.1.137	RhoGAP_dom, SH2, SH3_domain

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
cortical plate	2
adrenal tissue	1
tendon	1
leukocyte	1
monocyte	1
mononuclear cell	1
embryo	1
ganglionic eminence	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon
RIT1	268	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
AKT3	231	ubiquitous	marker	cortical plate, calcaneal tendon, embryo
PIK3R2	138	ubiquitous	marker	cortical plate, ganglionic eminence, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIK3CA	5,157
AKT3	3,392
RIT1	3,298
PIK3R2	2,751

Intra-cohort edges

A	B	Sources
AKT3	PIK3CA	string_interaction
AKT3	PIK3R2	string_interaction
PIK3CA	PIK3R2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3CA	P42336	135
PIK3R2	O00459	8
RIT1	Q92963	3
AKT3	Q9Y243	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 151. Enrichment computed across 4 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
CD28 dependent PI3K/Akt signaling	3	295.3×	9e-06	PIK3CA, AKT3, PIK3R2
Extra-nuclear estrogen signaling	3	127.8×	6e-05	PIK3CA, AKT3, PIK3R2
VEGFA-VEGFR2 Pathway	3	104.5×	7e-05	PIK3CA, AKT3, PIK3R2
Signaling by LTK in cancer	2	815.7×	7e-05	PIK3CA, PIK3R2
PI3K/AKT activation	2	634.4×	1e-04	PIK3CA, PIK3R2
IRS-mediated signalling	2	519.1×	1e-04	PIK3CA, PIK3R2
Co-stimulation by ICOS	2	519.1×	1e-04	PIK3CA, PIK3R2
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	2	439.2×	1e-04	PIK3CA, PIK3R2
Signaling by PDGFRA extracellular domain mutants	2	439.2×	1e-04	PIK3CA, PIK3R2
Signaling by LTK	2	439.2×	1e-04	PIK3CA, PIK3R2
PIP3 activates AKT signaling	3	50.1×	2e-04	PIK3CA, AKT3, PIK3R2
Tie2 Signaling	2	300.5×	2e-04	PIK3CA, PIK3R2
Role of LAT2/NTAL/LAB on calcium mobilization	2	300.5×	2e-04	PIK3CA, PIK3R2
Signaling by ALK	2	285.5×	2e-04	PIK3CA, PIK3R2
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	2	259.6×	2e-04	PIK3CA, PIK3R2
Regulation of signaling by CBL	2	248.3×	2e-04	PIK3CA, PIK3R2
Nephrin family interactions	2	237.9×	2e-04	PIK3CA, PIK3R2
Role of phospholipids in phagocytosis	2	228.4×	2e-04	PIK3CA, PIK3R2
Interleukin receptor SHC signaling	2	203.9×	3e-04	PIK3CA, PIK3R2
Downstream signal transduction	2	190.3×	3e-04	PIK3CA, PIK3R2
DAP12 signaling	2	184.2×	3e-04	PIK3CA, PIK3R2
FLT3 Signaling	2	173.0×	3e-04	PIK3CA, AKT3
Interleukin-3, Interleukin-5 and GM-CSF signaling	2	158.6×	4e-04	PIK3CA, PIK3R2
GPVI-mediated activation cascade	2	154.3×	4e-04	PIK3CA, PIK3R2
PI3K Cascade	2	135.9×	5e-04	PIK3CA, PIK3R2
RET signaling	2	129.8×	5e-04	PIK3CA, PIK3R2
Signaling by SCF-KIT	2	124.1×	5e-04	PIK3CA, PIK3R2
Synthesis of PIPs at the plasma membrane	2	105.7×	7e-04	PIK3CA, PIK3R2
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	2	80.4×	0.001	PIK3CA, PIK3R2
Signaling by ALK fusions and activated point mutants	2	75.1×	0.001	PIK3CA, PIK3R2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
insulin receptor signaling pathway	3	166.3×	3e-05	PIK3CA, AKT3, PIK3R2
positive regulation of TOR signaling	2	247.8×	9e-04	PIK3CA, AKT3
response to muscle inactivity	1	4213.0×	0.003	PIK3CA
response to butyrate	1	4213.0×	0.003	PIK3CA
phosphatidylinositol 3-kinase/protein kinase B signal transduction	2	105.3×	0.003	PIK3CA, PIK3R2
cellular response to insulin stimulus	2	85.1×	0.003	PIK3CA, PIK3R2
response to L-leucine	1	1404.3×	0.007	PIK3CA
cellular response to hydrostatic pressure	1	1404.3×	0.007	PIK3CA
positive regulation of artery morphogenesis	1	842.6×	0.009	AKT3
negative regulation of actin filament depolymerization	1	702.2×	0.009	PIK3CA
regulation of cellular respiration	1	702.2×	0.009	PIK3CA
regulation of actin filament organization	1	601.9×	0.009	PIK3CA
autosome genomic imprinting	1	601.9×	0.009	PIK3CA
negative regulation of fibroblast apoptotic process	1	601.9×	0.009	PIK3CA
cardiac muscle cell contraction	1	421.3×	0.011	PIK3CA
positive regulation of protein localization to membrane	1	421.3×	0.011	PIK3CA
TORC2 signaling	1	383.0×	0.011	PIK3CA
negative regulation of PERK-mediated unfolded protein response	1	351.1×	0.011	AKT3
phosphatidylinositol-3-phosphate biosynthetic process	1	324.1×	0.011	PIK3CA
anoikis	1	324.1×	0.011	PIK3CA
positive regulation of cell size	1	324.1×	0.011	AKT3
relaxation of cardiac muscle	1	324.1×	0.011	PIK3CA
response to dexamethasone	1	300.9×	0.011	PIK3CA
vasculature development	1	280.9×	0.011	PIK3CA
negative regulation of macroautophagy	1	280.9×	0.011	PIK3CA
vascular endothelial growth factor signaling pathway	1	263.3×	0.012	PIK3CA
regulation of stress fiber assembly	1	247.8×	0.012	PIK3R2
negative regulation of anoikis	1	221.7×	0.012	PIK3CA
regulation of mitochondrion organization	1	210.7×	0.012	AKT3
positive regulation of vascular endothelial cell proliferation	1	210.7×	0.012	AKT3

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
AKT3	CAPIVASERTIB
PIK3R2	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3CA	67	4
AKT3	18	4
PIK3R2	6	4
RIT1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDELALISIB	4	PIK3CA, PIK3R2
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, PIK3R2
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	AKT3, PIK3CA
CAPIVASERTIB	4	AKT3
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	AKT3, PIK3CA
TASELISIB	3	PIK3CA, PIK3R2
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	AKT3, PIK3CA
AFURESERTIB	3	AKT3
ENZASTAURIN	3	AKT3
FASUDIL	3	AKT3
RUBOXISTAURIN	3	AKT3
OMIPALISIB	2	PIK3CA
VISTUSERTIB	2	PIK3CA
FIMEPINOSTAT	2	PIK3CA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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
AKT3	660	Binding:644, Functional:16
PIK3R2	27	Binding:27

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
AKT3	2.7.11.1	non-specific serine/threonine protein kinase
PIK3R2	2.7.1.137	phosphatidylinositol 3-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
AKT3	660

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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, PIK3R2
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, PIK3R2
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	AKT3, PIK3CA
CAPIVASERTIB	4	AKT3
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	AKT3, PIK3CA
TASELISIB	3	PIK3CA, PIK3R2
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	AKT3, PIK3CA
AFURESERTIB	3	AKT3
ENZASTAURIN	3	AKT3
FASUDIL	3	AKT3
RUBOXISTAURIN	3	AKT3
OMIPALISIB	2	PIK3CA
VISTUSERTIB	2	PIK3CA
FIMEPINOSTAT	2	PIK3CA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	PIK3CA, AKT3, PIK3R2
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	RIT1

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)
RIT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05563831	Not specified	COMPLETED	National Evaluation of Patients With PIK3CA-Related Overgrowth Spectrum (PROS)