Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4

Summary

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4 (MONDO:0014104) is a disease caused by ATP8A2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ATP8A2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 67

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4
Mondo ID	MONDO:0014104
OMIM	615268
DOID	DOID:0070559
UMLS	C3808977
MedGen	815307
GARD	0015930
Is cancer (heuristic)	no

Also known as: ATP8A2 dysequilibrium syndrome · CAMRQ4 · cerebellar ataxia and mental retardation with or without quadrupedal locomotion 4 · cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4 · cerebellar ataxia, intellectual disability, and dysequilibrium syndrome type 4 · cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 · cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4 · dysequilibrium syndrome caused by mutation in ATP8A2

Data availability: 67 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › cerebellar ataxia, intellectual disability, and dysequilibrium › cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4

Related subtypes (3): cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2, cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3, cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1

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

67 retrieved; paginated sample, class counts are floors:

22 uncertain significance, 17 likely pathogenic, 11 pathogenic, 7 benign, 5 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033826	NM_016529.6(ATP8A2):c.77-2A>G	ATP8A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323964	NM_016529.6(ATP8A2):c.3272+1G>A	ATP8A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323981	NM_016529.6(ATP8A2):c.2212-1G>C	ATP8A2	Pathogenic	criteria provided, multiple submitters, no conflicts
1526029	NM_016529.6(ATP8A2):c.709del (p.Thr237fs)	ATP8A2	Pathogenic	criteria provided, single submitter
2444321	NM_016529.6(ATP8A2):c.1272T>G (p.Tyr424Ter)	ATP8A2	Pathogenic	criteria provided, single submitter
2628313	NM_016529.6(ATP8A2):c.1580-18C>G	ATP8A2	Pathogenic	no assertion criteria provided
3338257	NM_016529.6(ATP8A2):c.649C>T (p.Gln217Ter)	ATP8A2	Pathogenic	criteria provided, single submitter
3339979	NM_016529.6(ATP8A2):c.3316dup (p.Glu1106fs)	ATP8A2	Pathogenic	criteria provided, single submitter
426579	NM_016529.6(ATP8A2):c.1782+2T>C	ATP8A2	Pathogenic	criteria provided, multiple submitters, no conflicts
429349	NM_016529.6(ATP8A2):c.1756C>T (p.Arg586Ter)	ATP8A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
50946	NM_016529.6(ATP8A2):c.1128C>G (p.Ile376Met)	ATP8A2	Pathogenic	no assertion criteria provided
522073	NM_016529.6(ATP8A2):c.1761dup (p.Arg588fs)	ATP8A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800920	NM_016529.6(ATP8A2):c.1741C>T (p.Arg581Ter)	ATP8A2	Pathogenic	criteria provided, single submitter
802914	NM_016529.6(ATP8A2):c.2655del (p.Asn886fs)	ATP8A2	Pathogenic	criteria provided, single submitter
976733	NM_016529.6(ATP8A2):c.691_701del (p.Leu231fs)	ATP8A2	Pathogenic	criteria provided, single submitter
1029608	NM_016529.6(ATP8A2):c.2158C>T (p.Arg720Ter)	ATP8A2	Likely pathogenic	criteria provided, single submitter
1029609	NM_016529.6(ATP8A2):c.3469+1G>C	ATP8A2	Likely pathogenic	criteria provided, single submitter
1323963	NM_016529.6(ATP8A2):c.1474-2del	ATP8A2	Likely pathogenic	criteria provided, single submitter
1526205	NM_016529.6(ATP8A2):c.518del (p.Gly173fs)	ATP8A2	Likely pathogenic	criteria provided, single submitter
1804808	NM_016529.6(ATP8A2):c.2842A>T (p.Lys948Ter)	ATP8A2	Likely pathogenic	criteria provided, single submitter
2436153	NM_016529.6(ATP8A2):c.1322dup (p.Lys442fs)	ATP8A2	Likely pathogenic	criteria provided, single submitter
3065802	NM_016529.6(ATP8A2):c.3334C>T (p.Arg1112Ter)	ATP8A2	Likely pathogenic	criteria provided, single submitter
3242096	NM_016529.6(ATP8A2):c.780-1G>T	ATP8A2	Likely pathogenic	criteria provided, single submitter
3251779	NM_016529.6(ATP8A2):c.1287G>T (p.Lys429Asn)	ATP8A2	Likely pathogenic	criteria provided, single submitter
4077149	NM_016529.6(ATP8A2):c.2551dup (p.Asp851fs)	ATP8A2	Likely pathogenic	criteria provided, single submitter
418701	NM_016529.6(ATP8A2):c.2293G>T (p.Asp765Tyr)	ATP8A2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4796678	NM_016529.6(ATP8A2):c.2733G>A (p.Trp911Ter)	ATP8A2	Likely pathogenic	criteria provided, single submitter
800507	NM_016529.6(ATP8A2):c.1917T>A (p.Tyr639Ter)	ATP8A2	Likely pathogenic	criteria provided, single submitter
800921	NM_016529.6(ATP8A2):c.2749A>G (p.Asn917Asp)	ATP8A2	Likely pathogenic	no assertion criteria provided
812083	NM_016529.6(ATP8A2):c.1868-2A>G	ATP8A2	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ATP8A2	Strong	Autosomal recessive	cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP8A2	Orphanet:1766	Dysequilibrium 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
ATP8A2	HGNC:13533	ENSG00000132932	Q9NTI2	Phospholipid-transporting ATPase IB	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP8A2	Phospholipid-transporting ATPase IB	Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids from the outer to the inner leaflet of various membranes and ensures the maintenance of asymmetric dis…

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP8A2	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf

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
middle temporal gyrus	1
orbitofrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP8A2	180	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, orbitofrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP8A2	1,592

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP8A2	Q9NTI2	81.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Ion transport by P-type ATPases	1	207.6×	0.014	ATP8A2
Ion channel transport	1	96.0×	0.016	ATP8A2
Transport of small molecules	1	25.1×	0.040	ATP8A2

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
involuntary skeletal muscle contraction	1	16852.0×	0.001	ATP8A2
aminophospholipid translocation	1	8426.0×	0.001	ATP8A2
positive regulation of phospholipid translocation	1	4213.0×	0.001	ATP8A2
neurofilament cytoskeleton organization	1	1685.2×	0.003	ATP8A2
neuromuscular process controlling posture	1	1053.2×	0.003	ATP8A2
response to auditory stimulus	1	732.7×	0.003	ATP8A2
retina layer formation	1	648.1×	0.003	ATP8A2
detection of light stimulus involved in visual perception	1	648.1×	0.003	ATP8A2
phospholipid translocation	1	624.1×	0.003	ATP8A2
eating behavior	1	601.9×	0.003	ATP8A2
positive regulation of multicellular organism growth	1	495.6×	0.003	ATP8A2
skin development	1	443.5×	0.003	ATP8A2
determination of adult lifespan	1	432.1×	0.003	ATP8A2
inner ear morphogenesis	1	300.9×	0.004	ATP8A2
neuron development	1	255.3×	0.005	ATP8A2
axonogenesis	1	160.5×	0.007	ATP8A2
positive regulation of neuron projection development	1	137.0×	0.008	ATP8A2
negative regulation of cell population proliferation	1	42.1×	0.024	ATP8A2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP8A2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP8A2	7.6.2.1	P-type phospholipid transporter

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

0 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.

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	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	ATP8A2

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)
ATP8A2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.