Proteus syndrome

Summary

Proteus syndrome (MONDO:0008318) is a disease caused by AKT1 (GenCC Definitive), with 1 cohort gene and 6 clinical trials. Top therapeutic interventions include miransertib.

At a glance

• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: AKT1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 18
• Phenotypes (HPO): 115
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Validated
Prevalence at birth	<1 / 1 000 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0005306	Capillary hemangioma	Very frequent (80-99%)
HP:0007400	Irregular hyperpigmentation	Very frequent (80-99%)
HP:0007552	Abnormal subcutaneous fat tissue distribution	Very frequent (80-99%)
HP:0010816	Epidermal nevus	Very frequent (80-99%)
HP:0011276	Vascular skin abnormality	Very frequent (80-99%)
HP:0012032	Lipoma	Very frequent (80-99%)
HP:0100026	Arteriovenous malformation	Very frequent (80-99%)
HP:0100555	Asymmetric growth	Very frequent (80-99%)
HP:0100559	Lower limb asymmetry	Very frequent (80-99%)
HP:0100560	Upper limb asymmetry	Very frequent (80-99%)
HP:0100764	Lymphangioma	Very frequent (80-99%)
HP:0000995	Melanocytic nevus	Very frequent (80-99%)
HP:0001000	Abnormality of skin pigmentation	Very frequent (80-99%)
HP:0001072	Thickened skin	Very frequent (80-99%)
HP:0001167	Abnormality of finger	Very frequent (80-99%)
HP:0001482	Subcutaneous nodule	Very frequent (80-99%)
HP:0001519	Disproportionate tall stature	Very frequent (80-99%)
HP:0001548	Overgrowth	Very frequent (80-99%)
HP:0001555	Asymmetry of the thorax	Very frequent (80-99%)
HP:0002650	Scoliosis	Very frequent (80-99%)
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0002808	Kyphosis	Very frequent (80-99%)
HP:0003199	Decreased muscle mass	Very frequent (80-99%)
HP:0003312	Abnormal form of the vertebral bodies	Very frequent (80-99%)
HP:0004099	Macrodactyly	Very frequent (80-99%)
HP:0004326	Cachexia	Very frequent (80-99%)
HP:0004437	Cranial hyperostosis	Very frequent (80-99%)
HP:0000268	Dolichocephaly	Frequent (30-79%)
HP:0000311	Round face	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000400	Macrotia	Frequent (30-79%)
HP:0000896	Rib exostoses	Frequent (30-79%)
HP:0001004	Lymphedema	Frequent (30-79%)
HP:0002101	Abnormal lung lobation	Frequent (30-79%)
HP:0002204	Pulmonary embolism	Frequent (30-79%)
HP:0004418	Thrombophlebitis	Frequent (30-79%)
HP:0004459	Exostosis of the external auditory canal	Frequent (30-79%)
HP:0004490	Calvarial hyperostosis	Frequent (30-79%)
HP:0005595	Generalized hyperkeratosis	Frequent (30-79%)
HP:0006101	Finger syndactyly	Frequent (30-79%)
HP:0007565	Multiple cafe-au-lait spots	Frequent (30-79%)
HP:0009125	Lipodystrophy	Frequent (30-79%)
HP:0010566	Hamartoma	Frequent (30-79%)
HP:0012721	Venous malformation	Frequent (30-79%)
HP:0025104	Capillary malformation	Frequent (30-79%)
HP:0032445	Pulmonary cyst	Frequent (30-79%)
HP:0032446	Pulmonary bulla	Frequent (30-79%)
HP:0034275	Verrucous epidermal nevus	Frequent (30-79%)
HP:0100730	Bronchogenic cyst	Frequent (30-79%)
HP:0100761	Visceral angiomatosis	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Proteus syndrome
Mondo ID	MONDO:0008318
MeSH	D016715
OMIM	176920
Orphanet	744
DOID	DOID:13482
ICD-11	760267333
NCIT	C85032
SNOMED CT	23150001
UMLS	C0085261
MedGen	39008
GARD	0007475
NORD	1622
Is cancer (heuristic)	no

Also known as: Elattoproteus syndrome · gigantism, partial, of hands and feet, nevi, hemihypertrophy, and macrocephaly · hemihypertrophy and macrocephaly · partial gigantism of hands and feet, nevi, hemihypertrophy, macrocephaly · partial gigantism-nevi-hemihypertrophy-macrocephaly syndrome · Proteus syndrome · proteus syndrome, somatic · Wiedemann’s syndrome

Data availability: 18 ClinVar variants · 3 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › PTEN hamartoma tumor syndrome › Proteus syndrome

Related subtypes (3): Bannayan-Riley-Ruvalcaba syndrome, segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome, Proteus-like syndrome

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

18 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 2 pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
13983	NM_001382430.1(AKT1):c.49G>A (p.Glu17Lys)	AKT1	Pathogenic	criteria provided, multiple submitters, no conflicts
800567	NM_001382430.1(AKT1):c.49_50delinsAG (p.Glu17Arg)	AKT1	Pathogenic	criteria provided, single submitter
1685237	NM_001382430.1(AKT1):c.968A>G (p.Asp323Gly)	AKT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220815	NM_001382430.1(AKT1):c.1394G>A (p.Arg465His)	AKT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1395960	NM_001382430.1(AKT1):c.1036C>T (p.Arg346Cys)	AKT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1495054	NM_001382430.1(AKT1):c.511G>A (p.Ala171Thr)	AKT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2094919	NM_001382430.1(AKT1):c.176-3C>T	AKT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2416171	NM_001382430.1(AKT1):c.957+6C>T	AKT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3576482	NM_001382430.1(AKT1):c.237G>C (p.Gln79His)	AKT1	Uncertain significance	criteria provided, single submitter
3600497	NM_001382430.1(AKT1):c.1418_1420del (p.Ser473del)	AKT1	Uncertain significance	criteria provided, single submitter
410907	NM_001382430.1(AKT1):c.431G>A (p.Arg144His)	AKT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
473857	NM_001382430.1(AKT1):c.520C>T (p.Arg174Cys)	AKT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
540892	NM_001382430.1(AKT1):c.440T>C (p.Met147Thr)	AKT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
584876	NM_001382430.1(AKT1):c.176-5C>A	AKT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
847554	NM_001382430.1(AKT1):c.1260+5G>A	AKT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
853634	NM_001382430.1(AKT1):c.1289C>T (p.Thr430Met)	AKT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
955085	NM_001382430.1(AKT1):c.122G>A (p.Arg41Gln)	AKT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
240102	NM_001382430.1(AKT1):c.1032C>T (p.Cys344=)	AKT1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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
AKT1	Definitive	Autosomal dominant	Proteus syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AKT1	Orphanet:201	Cowden syndrome
AKT1	Orphanet:2495	Meningioma
AKT1	Orphanet:744	Proteus syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AKT1	HGNC:391	ENSG00000142208	P31749	RAC-alpha serine/threonine-protein kinase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AKT1	RAC-alpha serine/threonine-protein kinase	AKT1 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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AKT1	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, PH_domain

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
ganglionic eminence	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AKT1	273	ubiquitous	marker	stromal cell of endometrium, ganglionic eminence, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AKT1	16,601

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AKT1	P31749	43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 113. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
AKT-mediated inactivation of FOXO1A	1	2855.0×	0.007	AKT1
Inhibition of TSC complex formation by AKT (PKB)	1	2284.0×	0.007	AKT1
Metabolism of nitric oxide: NOS3 activation and regulation	1	2284.0×	0.007	AKT1
G-protein beta:gamma signalling	1	1903.3×	0.007	AKT1
Metabolism of cofactors	1	1903.3×	0.007	AKT1
RUNX2 regulates genes involved in cell migration	1	1427.5×	0.007	AKT1
PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1	1	1268.9×	0.007	AKT1
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	1	1142.0×	0.007	AKT1
AKT phosphorylates targets in the nucleus	1	1142.0×	0.007	AKT1
Regulation of localization of FOXO transcription factors	1	951.7×	0.007	AKT1
eNOS activation	1	878.5×	0.007	AKT1
SARS-CoV-2 targets host intracellular signalling and regulatory pathways	1	878.5×	0.007	AKT1
Downregulation of ERBB2:ERBB3 signaling	1	815.7×	0.007	AKT1
AKT phosphorylates targets in the cytosol	1	815.7×	0.007	AKT1
Regulation of TP53 Activity through Association with Co-factors	1	815.7×	0.007	AKT1
Activation of BAD and translocation to mitochondria	1	761.3×	0.007	AKT1
Regulation of mRNA stability by proteins that bind AU-rich elements	1	761.3×	0.007	AKT1
Regulation of beta-cell development	1	713.8×	0.007	AKT1
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	671.8×	0.007	AKT1
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	1	634.4×	0.007	AKT1
KSRP (KHSRP) binds and destabilizes mRNA	1	634.4×	0.007	AKT1
Mitochondrial unfolded protein response (UPRmt)	1	601.0×	0.007	AKT1
Signaling by PTK6	1	543.8×	0.007	AKT1
Signaling by Non-Receptor Tyrosine Kinases	1	543.8×	0.007	AKT1
Regulation of gene expression in beta cells	1	519.1×	0.007	AKT1
Co-inhibition by CTLA4	1	519.1×	0.007	AKT1
Regulation of TP53 Expression and Degradation	1	519.1×	0.007	AKT1
Activation of BH3-only proteins	1	496.5×	0.007	AKT1
Signaling by NOTCH4	1	496.5×	0.007	AKT1
Regulation of TP53 Activity through Acetylation	1	456.8×	0.007	AKT1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mammalian oogenesis stage	1	16852.0×	0.002	AKT1
positive regulation of endodeoxyribonuclease activity	1	16852.0×	0.002	AKT1
regulation of tRNA methylation	1	16852.0×	0.002	AKT1
negative regulation of protein maturation	1	16852.0×	0.002	AKT1
negative regulation of protein localization to lysosome	1	8426.0×	0.002	AKT1
cellular response to rapamycin	1	5617.3×	0.002	AKT1
negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway	1	5617.3×	0.002	AKT1
positive regulation of protein localization to endoplasmic reticulum	1	5617.3×	0.002	AKT1
negative regulation of long-chain fatty acid import across plasma membrane	1	4213.0×	0.002	AKT1
negative regulation of fatty acid beta-oxidation	1	4213.0×	0.002	AKT1
cellular response to decreased oxygen levels	1	4213.0×	0.002	AKT1
response to UV-A	1	4213.0×	0.002	AKT1
regulation of type B pancreatic cell development	1	4213.0×	0.002	AKT1
beta-arrestin-dependent dopamine receptor signaling pathway	1	3370.4×	0.002	AKT1
positive regulation of anaphase-promoting complex-dependent catabolic process	1	3370.4×	0.002	AKT1
negative regulation of lymphocyte migration	1	3370.4×	0.002	AKT1
interleukin-18-mediated signaling pathway	1	2808.7×	0.002	AKT1
obsolete establishment of protein localization to mitochondrion	1	2808.7×	0.002	AKT1
maintenance of protein location in mitochondrion	1	2808.7×	0.002	AKT1
negative regulation of leukocyte cell-cell adhesion	1	2808.7×	0.002	AKT1
response to insulin-like growth factor stimulus	1	2808.7×	0.002	AKT1
activation-induced cell death of T cells	1	2407.4×	0.002	AKT1
positive regulation of glucose metabolic process	1	2407.4×	0.002	AKT1
positive regulation of TORC2 signaling	1	2106.5×	0.003	AKT1
regulation of glycogen biosynthetic process	1	1872.4×	0.003	AKT1
response to fluid shear stress	1	1872.4×	0.003	AKT1
sphingosine-1-phosphate receptor signaling pathway	1	1685.2×	0.003	AKT1
cellular response to peptide	1	1685.2×	0.003	AKT1
maternal placenta development	1	1532.0×	0.003	AKT1
peripheral nervous system myelin maintenance	1	1532.0×	0.003	AKT1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

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

Symbol	Example approved molecule
AKT1	CAPIVASERTIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AKT1	30	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CAPIVASERTIB	4	AKT1
MILTEFOSINE	4	AKT1
NICLOSAMIDE	4	AKT1
MIDOSTAURIN	4	AKT1
IPATASERTIB	3	AKT1
AFURESERTIB	3	AKT1
LINIFANIB	3	AKT1
PERIFOSINE	3	AKT1
FASUDIL	3	AKT1
QUERCETIN	3	AKT1
LESTAURTINIB	3	AKT1
MIRANSERTIB	2	AKT1
MK-2206	2	AKT1
PF-04691502	2	AKT1
SULFAETHIDOLE	2	AKT1
KALAFUNGIN	2	AKT1
LAUROGUADINE	2	AKT1
EDELFOSINE	2	AKT1
UPROSERTIB	2	AKT1
RUPITASERTIB	2	AKT1
PICTILISIB	2	AKT1
SOTRASTAURIN	2	AKT1
ELLAGIC ACID	2	AKT1
AT-13148	1	AKT1
GSK-690693	1	AKT1
XL-418	1	AKT1
SAR-260301	1	AKT1
BAY-1125976	1	AKT1
VEVORISERTIB	1	AKT1
CYC-116	1	AKT1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
AKT1	1,942	Binding:1900, Functional:34, ADMET:7, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AKT1	2.7.11.1	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
AKT1	1,942

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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)
CAPIVASERTIB	4	AKT1
MILTEFOSINE	4	AKT1
NICLOSAMIDE	4	AKT1
MIDOSTAURIN	4	AKT1
IPATASERTIB	3	AKT1
AFURESERTIB	3	AKT1
LINIFANIB	3	AKT1
PERIFOSINE	3	AKT1
FASUDIL	3	AKT1
QUERCETIN	3	AKT1
LESTAURTINIB	3	AKT1
MK-2206	2	AKT1
PF-04691502	2	AKT1
SULFAETHIDOLE	2	AKT1
KALAFUNGIN	2	AKT1
LAUROGUADINE	2	AKT1
EDELFOSINE	2	AKT1
UPROSERTIB	2	AKT1
RUPITASERTIB	2	AKT1
PICTILISIB	2	AKT1
SOTRASTAURIN	2	AKT1
ELLAGIC ACID	2	AKT1
AT-13148	1	AKT1
GSK-690693	1	AKT1
XL-418	1	AKT1
SAR-260301	1	AKT1
BAY-1125976	1	AKT1
VEVORISERTIB	1	AKT1
CYC-116	1	AKT1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	AKT1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE1/PHASE2	1
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04316546	PHASE2	ACTIVE_NOT_RECRUITING	MK-7075 (Miransertib) in Proteus Syndrome
NCT03094832	PHASE1/PHASE2	TERMINATED	Study of Miransertib (MK-7075) in Participants With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome (MOSAIC) (MK-7075-002)
NCT02594215	PHASE1	COMPLETED	Dose Finding Trial of MK-7075 in Children and Adults With Proteus Syndrome
NCT00001403	Not specified	RECRUITING	Study of Proteus Syndrome and Related Congenital Disorders
NCT01369953	Not specified	COMPLETED	Informed Consent for Whole Genome Sequencing: Ideals and Norms Referenced by Early Participants
NCT03317366	Not specified	NO_LONGER_AVAILABLE	Expanded Access to Provide ARQ 092 for the Treatment of Overgrowth Diseases and/or Vascular Anomalies

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MIRANSERTIB	2	2