Developmental and epileptic encephalopathy 91

Summary

Developmental and epileptic encephalopathy 91 (MONDO:0020630) is a disease caused by PPP3CA (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PPP3CA (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 88

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy 91
Mondo ID	MONDO:0020630
OMIM	617711
DOID	DOID:0080472
UMLS	C4540199
MedGen	1626137
GARD	0025189
Is cancer (heuristic)	no

Also known as: DEE91 · developmental and epileptic encephalopathy 91 · epileptic encephalopathy, infantile or early childhood, 1 · IECEE1

Data availability: 88 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › Mendelian neurodevelopmental disorder › genetic developmental and epileptic encephalopathy › developmental and epileptic encephalopathy 91

Related subtypes (104): developmental and epileptic encephalopathy, 9, developmental and epileptic encephalopathy, 8, developmental and epileptic encephalopathy, 2, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, developmental and epileptic encephalopathy, 1, developmental and epileptic encephalopathy, 3, developmental and epileptic encephalopathy, 4, microcephaly, seizures, and developmental delay, developmental and epileptic encephalopathy, 5, developmental and epileptic encephalopathy, 7, developmental and epileptic encephalopathy, 11, neonatal-onset encephalopathy with rigidity and seizures, developmental and epileptic encephalopathy, 14, developmental and epileptic encephalopathy, 15, developmental and epileptic encephalopathy, 17, developmental and epileptic encephalopathy, 18, developmental and epileptic encephalopathy, 19, developmental and epileptic encephalopathy, 23, developmental and epileptic encephalopathy, 27, developmental and epileptic encephalopathy, 30, developmental and epileptic encephalopathy, 50, developmental and epileptic encephalopathy, 35, developmental and epileptic encephalopathy, 37, developmental and epileptic encephalopathy, 38, developmental and epileptic encephalopathy, 40, developmental and epileptic encephalopathy, 48, developmental and epileptic encephalopathy, 49, developmental and epileptic encephalopathy, 51, Lennox-Gastaut syndrome, developmental and epileptic encephalopathy 92, developmental and epileptic encephalopathy 93, developmental and epileptic encephalopathy 96, developmental and epileptic encephalopathy, 90, developmental and epileptic encephalopathy, 85, with or without midline brain defects, developmental and epileptic encephalopathy, 67, developmental and epileptic encephalopathy, 86, developmental and epileptic encephalopathy, 87, developmental and epileptic encephalopathy, 88, developmental and epileptic encephalopathy 6B, developmental and epileptic encephalopathy 97, developmental and epileptic encephalopathy 98, developmental and epileptic encephalopathy 99, developmental and epileptic encephalopathy 100, developmental and epileptic encephalopathy 101, developmental and epileptic encephalopathy 89, developmental and epileptic encephalopathy 102, developmental and epileptic encephalopathy 103, developmental and epileptic encephalopathy 104, developmental and epileptic encephalopathy 105 with hypopituitarism, developmental and epileptic encephalopathy 106, developmental and epileptic encephalopathy 107, developmental and epileptic encephalopathy, 68, developmental and epileptic encephalopathy, 69, developmental and epileptic encephalopathy, 70, developmental and epileptic encephalopathy, 71, developmental and epileptic encephalopathy, 72, developmental and epileptic encephalopathy, 74, developmental and epileptic encephalopathy, 75, developmental and epileptic encephalopathy, 76, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 78, developmental and epileptic encephalopathy, 79, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 81, developmental and epileptic encephalopathy, 82, developmental and epileptic encephalopathy, 83, developmental and epileptic encephalopathy, 84, developmental and epileptic encephalopathy, 52, developmental and epileptic encephalopathy, 53, developmental and epileptic encephalopathy, 54, developmental and epileptic encephalopathy, 55, developmental and epileptic encephalopathy, 56, developmental and epileptic encephalopathy, 57, developmental and epileptic encephalopathy, 58, developmental and epileptic encephalopathy, 59, developmental and epileptic encephalopathy, 60, developmental and epileptic encephalopathy, 61, developmental and epileptic encephalopathy, 62, developmental and epileptic encephalopathy, 63, developmental and epileptic encephalopathy, 64, developmental and epileptic encephalopathy, 65, developmental and epileptic encephalopathy, 73, developmental and epileptic encephalopathy, 66, developmental and epileptic encephalopathy, 6A, non-neonatal early infantile epileptic encephalopathy, Dravet syndrome, neonatal-onset developmental and epileptic encephalopathy, hemiplegic migraine-developmental and epileptic encephalopathy spectrum, DNM1-encephalopathy and neurodevelopmental disorder, TMEM63B-related developmental and epileptic encephalopathy with anemia, developmental and epileptic encephalopathy 108, developmental and epileptic encephalopathy 109, developmental and epileptic encephalopathy 110, developmental and epileptic encephalopathy 111, developmental and epileptic encephalopathy 112, developmental and epileptic encephalopathy 113, developmental and epileptic encephalopathy 114, developmental and epileptic encephalopathy 115, developmental and epileptic encephalopathy 116, developmental and epileptic encephalopathy 118, developmental and epileptic encephalopathy 120, developmental and epileptic encephalopathy 121, developmental and epileptic encephalopathy 119

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

88 retrieved; paginated sample, class counts are floors:

34 uncertain significance, 13 pathogenic, 12 benign/likely benign, 10 likely benign, 7 likely pathogenic, 6 pathogenic/likely pathogenic, 5 conflicting classifications of pathogenicity, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064702	NM_000944.5(PPP3CA):c.1299dup (p.Ser434fs)	PPP3CA	Pathogenic	criteria provided, single submitter
1452512	NM_000944.5(PPP3CA):c.702C>A (p.Asp234Glu)	PPP3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686095	NM_000944.5(PPP3CA):c.762G>T (p.Arg254Ser)	PPP3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1703173	NM_000944.5(PPP3CA):c.1251_1252del (p.Ser417fs)	PPP3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
3236340	NM_000944.5(PPP3CA):c.1308_1312dup (p.Ser438fs)	PPP3CA	Pathogenic	criteria provided, single submitter
3900639	NM_000944.5(PPP3CA):c.1354_1356delinsCAATA (p.Ile452fs)	PPP3CA	Pathogenic	criteria provided, single submitter
3900641	NM_000944.5(PPP3CA):c.1284_1287dup (p.Gly430fs)	PPP3CA	Pathogenic	criteria provided, single submitter
3900642	NM_000944.5(PPP3CA):c.1333_1336dup (p.Ser446fs)	PPP3CA	Pathogenic	criteria provided, single submitter
3900643	NM_000944.5(PPP3CA):c.1338dup (p.Ala447fs)	PPP3CA	Pathogenic	criteria provided, single submitter
3900644	NM_000944.5(PPP3CA):c.1255_1258dup (p.Val420fs)	PPP3CA	Pathogenic	criteria provided, single submitter
441271	NM_000944.5(PPP3CA):c.1333C>T (p.Gln445Ter)	PPP3CA	Pathogenic	no assertion criteria provided
441272	NM_000944.5(PPP3CA):c.275A>G (p.His92Arg)	PPP3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
441273	NM_000944.5(PPP3CA):c.1339G>A (p.Ala447Thr)	PPP3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
441275	NM_000944.5(PPP3CA):c.844G>A (p.Glu282Lys)	PPP3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496636	NM_000944.5(PPP3CA):c.1255_1256del (p.Ser419fs)	PPP3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
522802	NM_000944.5(PPP3CA):c.1308_1311dup (p.Ser438fs)	PPP3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
599239	NM_000944.5(PPP3CA):c.1290dup (p.Met431fs)	PPP3CA	Pathogenic	no assertion criteria provided
802080	NM_000944.5(PPP3CA):c.1311_1315del (p.Ser438fs)	PPP3CA	Pathogenic	criteria provided, single submitter
931475	NM_000944.5(PPP3CA):c.1283dup (p.Thr429fs)	PPP3CA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343236	NM_000944.5(PPP3CA):c.34_43del (p.Ser12fs)	PPP3CA	Likely pathogenic	criteria provided, single submitter
1694451	NM_000944.5(PPP3CA):c.530C>G (p.Ala177Gly)	PPP3CA	Likely pathogenic	criteria provided, single submitter
3900640	NM_000944.5(PPP3CA):c.1375A>T (p.Lys459Ter)	PPP3CA	Likely pathogenic	criteria provided, single submitter
4277452	NM_000944.5(PPP3CA):c.1340-2A>C	PPP3CA	Likely pathogenic	criteria provided, single submitter
441274	NM_000944.5(PPP3CA):c.843C>G (p.His281Gln)	PPP3CA	Likely pathogenic	criteria provided, single submitter
4813743	NM_000944.5(PPP3CA):c.353A>G (p.Asp118Gly)	PPP3CA	Likely pathogenic	criteria provided, single submitter
812184	NM_000944.5(PPP3CA):c.1477G>A (p.Asp493Asn)	PPP3CA	Likely pathogenic	criteria provided, single submitter
1437265	NM_000944.5(PPP3CA):c.1082-5T>G	PPP3CA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1474325	NM_000944.5(PPP3CA):c.1538A>G (p.Asn513Ser)	PPP3CA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1562032	NM_000944.5(PPP3CA):c.345C>T (p.Phe115=)	PPP3CA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1981080	NM_000944.5(PPP3CA):c.25C>A (p.Pro9Thr)	PPP3CA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
PPP3CA	Strong	Autosomal dominant	developmental and epileptic encephalopathy 91	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PPP3CA	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
PPP3CA	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
PPP3CA	Orphanet:565858	Craniosynostosis-microretrognathia-severe intellectual disability 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
PPP3CA	HGNC:9314	ENSG00000138814	Q08209	Protein phosphatase 3 catalytic subunit alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PPP3CA	Protein phosphatase 3 catalytic subunit alpha	Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals.

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
Phosphatase	1	83.9×	0.012

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PPP3CA	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.

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
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PPP3CA	291	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PPP3CA	4,486

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PPP3CA	Q08209	21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Calcineurin activates NFAT	1	1268.9×	0.002	PPP3CA
CLEC7A (Dectin-1) induces NFAT activation	1	1038.2×	0.002	PPP3CA
DARPP-32 events	1	475.8×	0.004	PPP3CA
FCERI mediated Ca+2 mobilization	1	356.9×	0.004	PPP3CA
Ca2+ pathway	1	178.4×	0.006	PPP3CA

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
regulation of cell proliferation involved in kidney morphogenesis	1	16852.0×	8e-04	PPP3CA
negative regulation of angiotensin-activated signaling pathway	1	16852.0×	8e-04	PPP3CA
negative regulation of signaling	1	8426.0×	8e-04	PPP3CA
positive regulation of glomerulus development	1	8426.0×	8e-04	PPP3CA
positive regulation of saliva secretion	1	5617.3×	8e-04	PPP3CA
peptidyl-serine dephosphorylation	1	5617.3×	8e-04	PPP3CA
renal filtration	1	5617.3×	8e-04	PPP3CA
positive regulation of calcium ion-dependent exocytosis of neurotransmitter	1	5617.3×	8e-04	PPP3CA
positive regulation of cardiac muscle hypertrophy in response to stress	1	5617.3×	8e-04	PPP3CA
positive regulation of connective tissue replacement	1	5617.3×	8e-04	PPP3CA
negative regulation of calcium ion import across plasma membrane	1	3370.4×	0.001	PPP3CA
transition between fast and slow fiber	1	2407.4×	0.002	PPP3CA
negative regulation of dendrite morphogenesis	1	1872.4×	0.002	PPP3CA
positive regulation of calcium ion import across plasma membrane	1	1685.2×	0.002	PPP3CA
calcineurin-mediated signaling	1	1532.0×	0.002	PPP3CA
multicellular organismal response to stress	1	1296.3×	0.002	PPP3CA
cardiac muscle hypertrophy in response to stress	1	1053.2×	0.002	PPP3CA
skeletal muscle tissue regeneration	1	887.0×	0.003	PPP3CA
calcineurin-NFAT signaling cascade	1	842.6×	0.003	PPP3CA
positive regulation of endocytosis	1	802.5×	0.003	PPP3CA
positive regulation of calcineurin-NFAT signaling cascade	1	802.5×	0.003	PPP3CA
dephosphorylation	1	674.1×	0.003	PPP3CA
positive regulation of activated T cell proliferation	1	674.1×	0.003	PPP3CA
postsynaptic modulation of chemical synaptic transmission	1	674.1×	0.003	PPP3CA
positive regulation of osteoclast differentiation	1	581.1×	0.003	PPP3CA
skeletal muscle fiber development	1	543.6×	0.003	PPP3CA
excitatory postsynaptic potential	1	443.5×	0.004	PPP3CA
dendrite morphogenesis	1	432.1×	0.004	PPP3CA
response to calcium ion	1	318.0×	0.005	PPP3CA
positive regulation of cell adhesion	1	271.8×	0.005	PPP3CA

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
PPP3CA	ZINC CHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PPP3CA	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ZINC CHLORIDE	4	PPP3CA
CYCLOSPORINE	4	PPP3CA
TACROLIMUS ANHYDROUS	4	PPP3CA
TAMOXIFEN	4	PPP3CA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PPP3CA	24	Binding:24

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PPP3CA	3.1.3.16	protein-serine/threonine phosphatase

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

4 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)
ZINC CHLORIDE	4	PPP3CA
CYCLOSPORINE	4	PPP3CA
TACROLIMUS ANHYDROUS	4	PPP3CA
TAMOXIFEN	4	PPP3CA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PPP3CA
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: 0.