Developmental and epileptic encephalopathy, 56

disease

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Also known as DEE56developmental and epileptic encephalopathy 56EIEE56epileptic encephalopathy, early infantile, 56infantile epileptic encephalopathy 56

Summary

Developmental and epileptic encephalopathy, 56 (MONDO:0033365) is a disease caused by YWHAG (GenCC Definitive), with 1 cohort gene.

At a glance

Causal gene: YWHAG (GenCC Definitive)
Cohort genes: 1
ClinVar variants: 23

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	developmental and epileptic encephalopathy, 56
Mondo ID	MONDO:0033365
OMIM	617665
DOID	DOID:0080282
UMLS	C4540034
MedGen	1621755
GARD	0025795
Is cancer (heuristic)	no

Also known as: DEE56 · developmental and epileptic encephalopathy 56 · EIEE56 · epileptic encephalopathy, early infantile, 56 · infantile epileptic encephalopathy 56

Data availability: 23 ClinVar variants · 4 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, 56

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

23 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 4 likely pathogenic, 4 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 2 pathogenic, 1 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1338767	NM_012479.4(YWHAG):c.170G>A (p.Arg57His)	YWHAG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1439308	NM_012479.4(YWHAG):c.124C>T (p.Arg42Ter)	YWHAG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438804	NM_012479.4(YWHAG):c.394C>T (p.Arg132Cys)	YWHAG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438806	NM_012479.4(YWHAG):c.387C>G (p.Asp129Glu)	YWHAG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
659092	NM_012479.4(YWHAG):c.169C>T (p.Arg57Cys)	YWHAG	Pathogenic	criteria provided, multiple submitters, no conflicts
802325	NM_012479.4(YWHAG):c.451G>T (p.Glu151Ter)	YWHAG	Pathogenic	criteria provided, single submitter
1027791	NM_012479.4(YWHAG):c.683A>T (p.Asp228Val)	YWHAG	Likely pathogenic	criteria provided, single submitter
2584359	NM_012479.4(YWHAG):c.628_642del (p.Thr210_Asp214del)	YWHAG	Likely pathogenic	criteria provided, single submitter
3339914	NC_000007.13:g.(?75956115)(75988309_?)del	YWHAG	Likely pathogenic	criteria provided, single submitter
3359022	NM_012479.4(YWHAG):c.532A>G (p.Asn178Asp)	YWHAG	Likely pathogenic	criteria provided, single submitter
2418754	NM_012479.4(YWHAG):c.578C>T (p.Ala193Val)	YWHAG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
549482	NM_012479.4(YWHAG):c.398A>C (p.Tyr133Ser)	YWHAG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
807723	NM_012479.4(YWHAG):c.395G>A (p.Arg132His)	YWHAG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1691492	NM_012479.4(YWHAG):c.62A>G (p.Asp21Gly)	YWHAG	Uncertain significance	criteria provided, single submitter
1696737	NM_012479.4(YWHAG):c.80T>G (p.Met27Arg)	YWHAG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709160	NM_012479.4(YWHAG):c.82A>G (p.Lys28Glu)	YWHAG	Uncertain significance	criteria provided, single submitter
3901208	NM_012479.4(YWHAG):c.461A>G (p.Tyr154Cys)	YWHAG	Uncertain significance	criteria provided, single submitter
4076333	NM_012479.4(YWHAG):c.137C>A (p.Ser46Tyr)	YWHAG	Uncertain significance	criteria provided, single submitter
4277555	NM_012479.4(YWHAG):c.691dup (p.Thr231fs)	YWHAG	Uncertain significance	criteria provided, single submitter
438805	NM_012479.4(YWHAG):c.44A>C (p.Glu15Ala)	YWHAG	Uncertain significance	criteria provided, single submitter
549487	NM_012479.4(YWHAG):c.148A>C (p.Lys50Gln)	YWHAG	Uncertain significance	criteria provided, single submitter
1676795	NM_012479.4(YWHAG):c.722A>G (p.Asp241Gly)	YWHAG	Likely benign	criteria provided, single submitter
707493	NM_012479.4(YWHAG):c.726C>T (p.Gly242=)	YWHAG	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
YWHAG	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 56	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
YWHAG	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

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
YWHAG	HGNC:12852	ENSG00000170027	P61981	14-3-3 protein gamma	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
YWHAG	14-3-3 protein gamma	Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
YWHAG	Other/Unknown	no		14-3-3, 14-3-3_CS, 14-3-3_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
lateral nuclear group of thalamus	1
pons	1
substantia nigra pars compacta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
YWHAG	266	ubiquitous	marker	lateral nuclear group of thalamus, pons, substantia nigra pars compacta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
YWHAG	3,643

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
YWHAG	P61981	22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 54. 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
Regulation of localization of FOXO transcription factors	1	951.7×	0.015	YWHAG
SARS-CoV-2 targets host intracellular signalling and regulatory pathways	1	878.5×	0.015	YWHAG
Activation of BAD and translocation to mitochondria	1	761.3×	0.015	YWHAG
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	1	671.8×	0.015	YWHAG
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	1	671.8×	0.015	YWHAG
Activation of BH3-only proteins	1	496.5×	0.015	YWHAG
FOXO-mediated transcription	1	335.9×	0.015	YWHAG
RHO GTPases activate PKNs	1	317.2×	0.015	YWHAG
Intrinsic Pathway for Apoptosis	1	292.8×	0.015	YWHAG
Centrosome maturation	1	253.8×	0.015	YWHAG
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	228.4×	0.015	YWHAG
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.015	YWHAG
SARS-CoV-1-host interactions	1	175.7×	0.015	YWHAG
Apoptosis	1	167.9×	0.015	YWHAG
Loss of Nlp from mitotic centrosomes	1	158.6×	0.015	YWHAG
Loss of proteins required for interphase microtubule organization from the centrosome	1	158.6×	0.015	YWHAG
Translocation of SLC2A4 (GLUT4) to the plasma membrane	1	154.3×	0.015	YWHAG
AURKA Activation by TPX2	1	152.3×	0.015	YWHAG
Programmed Cell Death	1	146.4×	0.015	YWHAG
SARS-CoV-1 Infection	1	142.8×	0.015	YWHAG
Recruitment of mitotic centrosome proteins and complexes	1	135.9×	0.015	YWHAG
G2/M Checkpoints	1	134.3×	0.015	YWHAG
TP53 Regulates Metabolic Genes	1	129.8×	0.015	YWHAG
Regulation of PLK1 Activity at G2/M Transition	1	126.9×	0.015	YWHAG
Mitotic G2-G2/M phases	1	126.9×	0.015	YWHAG
G2/M Transition	1	126.9×	0.015	YWHAG
G2/M DNA damage checkpoint	1	120.2×	0.015	YWHAG
SARS-CoV-2-host interactions	1	119.0×	0.015	YWHAG
Recruitment of NuMA to mitotic centrosomes	1	116.5×	0.015	YWHAG
MITF-M-regulated melanocyte development	1	114.2×	0.015	YWHAG

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of T cell mediated immune response to tumor cell	1	2407.4×	0.005	YWHAG
negative regulation of protein kinase activity	1	842.6×	0.005	YWHAG
positive regulation of cell-cell adhesion	1	766.0×	0.005	YWHAG
regulation of neuron differentiation	1	732.7×	0.005	YWHAG
positive regulation of T cell activation	1	443.5×	0.005	YWHAG
protein targeting	1	366.4×	0.005	YWHAG
cellular response to glucose starvation	1	337.0×	0.005	YWHAG
negative regulation of TORC1 signaling	1	324.1×	0.005	YWHAG
regulation of signal transduction	1	267.5×	0.005	YWHAG
regulation of synaptic plasticity	1	259.3×	0.005	YWHAG
regulation of protein localization	1	205.5×	0.006	YWHAG
cellular response to insulin stimulus	1	170.2×	0.007	YWHAG
intracellular protein localization	1	104.7×	0.010	YWHAG
signal transduction	1	16.1×	0.062	YWHAG

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
YWHAG	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	YWHAG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
YWHAG	12	Binding:11, Functional:1

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

1 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)
MOLIBRESIB	2	YWHAG

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	YWHAG
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.

Cohort genes: YWHAG