MONDO:0100025

Summary

MONDO:0100025 (MONDO:0100025) is a disease caused by SLC12A5 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: SLC12A5 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Mondo ID	MONDO:0100025
Is cancer (heuristic)	no

Data availability: 6 ClinVar variants · 1 GenCC gene-disease record.

Disease family

No broader Mondo term or subtypes recorded for this disease.

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

6 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1707403	GRCh38/hg38 2q24.3(chr2:165155128-166062451)x1	LOC126806396	Pathogenic	criteria provided, single submitter
1000049	NM_001040142.2(SCN2A):c.4901G>T (p.Gly1634Val)	SCN2A	Pathogenic	criteria provided, single submitter
1300201	NM_001040142.2(SCN2A):c.4018G>A (p.Val1340Ile)	SCN2A	Pathogenic	criteria provided, single submitter
206981	NM_001040142.2(SCN2A):c.2995G>A (p.Glu999Lys)	SCN2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207019	NM_001040142.2(SCN2A):c.4886G>A (p.Arg1629His)	SCN2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1708032	NM_001040142.2(SCN2A):c.2896G>C (p.Val966Leu)	SCN2A	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 9 · 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
SLC12A5	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 34	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC12A5	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN2A	Orphanet:140927	Self-limited neonatal-infantile epilepsy
SCN2A	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN2A	Orphanet:2131	Alternating hemiplegia of childhood
SCN2A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN2A	Orphanet:306	Self-limited infantile epilepsy
SCN2A	Orphanet:33069	Dravet syndrome
SCN2A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN2A	Orphanet:697160	Infantile epileptic spasms syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC12A5	HGNC:13818	ENSG00000124140	Q9H2X9	Solute carrier family 12 member 5	gencc
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC12A5	Solute carrier family 12 member 5	Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl(-) homeostasis.
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Ion channel	1	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC12A5	Other/Unknown	no		KCL_cotranspt, AA-permease/SLC12A_dom, SLC12A_fam
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
Brodmann (1909) area 23	1
cerebellar vermis	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC12A5	205	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCN2A	2,810
SLC12A5	2,287

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN2A	Q99250	5
SLC12A5	Q9H2X9	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cation-coupled Chloride cotransporters	1	815.7×	0.018	SLC12A5
Interaction between L1 and Ankyrins	1	184.2×	0.022	SCN2A
Phase 0 - rapid depolarisation	1	173.0×	0.022	SCN2A
Sensory perception of taste	1	167.9×	0.022	SCN2A
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	139.3×	0.022	SCN2A
R-HSA-425393	1	64.9×	0.034	SLC12A5
L1CAM interactions	1	60.1×	0.034	SCN2A
Cardiac conduction	1	54.4×	0.034	SCN2A
Sensory Perception	1	47.6×	0.035	SCN2A
Muscle contraction	1	38.6×	0.039	SCN2A
SLC-mediated transmembrane transport	1	29.6×	0.046	SLC12A5
Axon guidance	1	22.6×	0.053	SCN2A
Nervous system development	1	21.5×	0.053	SCN2A
Transport of small molecules	1	12.6×	0.083	SLC12A5
Developmental Biology	1	7.2×	0.134	SCN2A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hypotonic response	1	4213.0×	0.002	SLC12A5
intrinsic apoptotic signaling pathway in response to osmotic stress	1	4213.0×	0.002	SCN2A
thermosensory behavior	1	4213.0×	0.002	SLC12A5
postsynaptic neurotransmitter receptor diffusion trapping	1	1053.2×	0.006	SLC12A5
intracellular chloride ion homeostasis	1	842.6×	0.006	SLC12A5
chloride ion homeostasis	1	766.0×	0.006	SLC12A5
intracellular pH reduction	1	601.9×	0.006	SLC12A5
dendritic spine development	1	601.9×	0.006	SLC12A5
potassium ion homeostasis	1	383.0×	0.008	SLC12A5
cardiac muscle cell action potential involved in contraction	1	351.1×	0.008	SCN2A
cell volume homeostasis	1	300.9×	0.008	SLC12A5
neuronal action potential	1	240.7×	0.009	SCN2A
potassium ion import across plasma membrane	1	183.2×	0.011	SLC12A5
regulation of postsynapse assembly	1	172.0×	0.011	SLC12A5
learning	1	140.4×	0.012	SLC12A5
sodium ion transport	1	135.9×	0.012	SCN2A
myelination	1	125.8×	0.013	SCN2A
chloride transmembrane transport	1	118.7×	0.013	SLC12A5
sodium ion transmembrane transport	1	101.5×	0.014	SCN2A
neuron apoptotic process	1	92.6×	0.014	SCN2A
memory	1	91.6×	0.014	SCN2A
monoatomic ion transport	1	78.0×	0.016	SLC12A5
multicellular organism growth	1	68.5×	0.017	SLC12A5
cellular response to hypoxia	1	60.6×	0.018	SCN2A
chemical synaptic transmission	1	38.6×	0.028	SLC12A5
response to xenobiotic stimulus	1	34.5×	0.030	SLC12A5
nervous system development	1	23.0×	0.043	SCN2A

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
SCN2A	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
SLC12A5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	SCN2A
DROPERIDOL	4	SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	SCN2A
NIFEDIPINE	4	SCN2A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	SCN2A
PRENYLAMINE	4	SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A
CINNARIZINE	4	SCN2A
THIORIDAZINE	4	SCN2A
ETIDOCAINE	4	SCN2A
CHLORPHENIRAMINE	4	SCN2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
SLC12A5	6	Functional:4, Binding:2

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN2A	203

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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)
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	SCN2A
DROPERIDOL	4	SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	SCN2A
NIFEDIPINE	4	SCN2A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	SCN2A
PRENYLAMINE	4	SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A
CINNARIZINE	4	SCN2A
THIORIDAZINE	4	SCN2A
ETIDOCAINE	4	SCN2A
CHLORPHENIRAMINE	4	SCN2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN2A
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	SLC12A5

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)
SLC12A5	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.