Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3

Summary

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3 (MONDO:0013188) is a disease caused by CA8 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: CA8 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3
Mondo ID	MONDO:0013188
MeSH	C567690
OMIM	613227
DOID	DOID:0070558
UMLS	C2750509
MedGen	442496
GARD	0015634
Is cancer (heuristic)	no

Also known as: CA8 dysequilibrium syndrome · CAMRQ3 · cerebellar ataxia and mental retardation with or without quadrupedal locomotion 3 · cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3 · cerebellar ataxia, intellectual disability, and dysequilibrium syndrome type 3 · cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 · cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 3 · dysequilibrium syndrome caused by mutation in CA8

Data availability: 16 ClinVar variants · 2 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 3

Related subtypes (3): cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2, cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4, 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

16 retrieved; paginated sample, class counts are floors:

5 pathogenic, 5 likely pathogenic, 4 benign, 1 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17604	NM_004056.6(CA8):c.298T>C (p.Ser100Pro)	CA8	Pathogenic	no assertion criteria provided
29620	NM_004056.6(CA8):c.710G>A (p.Arg237Gln)	CA8	Pathogenic	no assertion criteria provided
3335814	NM_004056.6(CA8):c.484G>A (p.Gly162Arg)	CA8	Pathogenic	no assertion criteria provided
3335815	NM_004056.6(CA8):c.232C>T (p.Arg78Ter)	CA8	Pathogenic	no assertion criteria provided
3335816	NM_004056.6(CA8):c.251A>G (p.Asn84Ser)	CA8	Pathogenic	no assertion criteria provided
50503	NM_014489.4(PGAP2):c.713G>C (p.Arg238Pro)	PGAP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3773813	NM_004056.6(CA8):c.823C>T (p.Arg275Trp)	CA8	Likely pathogenic	criteria provided, single submitter
3897866	NM_004056.6(CA8):c.251A>C (p.Asn84Thr)	CA8	Likely pathogenic	criteria provided, single submitter
522600	NM_004056.6(CA8):c.475A>T (p.Lys159Ter)	CA8	Likely pathogenic	criteria provided, single submitter
560540	NM_004056.6(CA8):c.100+1G>A	CA8	Likely pathogenic	no assertion criteria provided
931983	NM_004056.6(CA8):c.730dup (p.Gln244fs)	CA8	Likely pathogenic	criteria provided, single submitter
4291965	NM_004056.6(CA8):c.699G>T (p.Trp233Cys)	CA8	Uncertain significance	criteria provided, single submitter
1192673	NM_004056.6(CA8):c.100+85T>C	CA8	Benign	criteria provided, multiple submitters, no conflicts
1192674	NM_004056.6(CA8):c.-54A>C	CA8	Benign	criteria provided, multiple submitters, no conflicts
1192675	NM_004056.6(CA8):c.-103T>C	CA8	Benign	criteria provided, multiple submitters, no conflicts
128540	NM_004056.6(CA8):c.327A>G (p.Glu109=)	CA8	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 2 · 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
CA8	Definitive	Autosomal recessive	cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CA8	Orphanet:1766	Dysequilibrium syndrome
PGAP2	Orphanet:247262	Hyperphosphatasia-intellectual disability 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
CA8	HGNC:1382	ENSG00000178538	P35219	Carbonic anhydrase-related protein	gencc,clinvar
PGAP2	HGNC:17893	ENSG00000148985	Q9UHJ9	Acyltransferase PGAP2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CA8	Carbonic anhydrase-related protein	Does not have a carbonic anhydrase catalytic activity.
PGAP2	Acyltransferase PGAP2	Involved in the fatty acid remodeling steps of GPI-anchor maturation where the unsaturated acyl chain at sn-2 of inositol phosphate is replaced by a saturated stearoyl chain.

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CA8	Enzyme (other)	yes	4.2.1.1	CA_dom, Carbonic_anhydrase_a-class_CS, Carbonic_anhydrase_a-class
PGAP2	Other/Unknown	no		CWH43_N, PGAP2

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
metanephros cortex	1
primordial germ cell in gonad	1
right hemisphere of cerebellum	1
corpus epididymis	1
lower esophagus mucosa	1
skin of abdomen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CA8	184	broad	marker	metanephros cortex, right hemisphere of cerebellum, primordial germ cell in gonad
PGAP2	280	ubiquitous	marker	corpus epididymis, lower esophagus mucosa, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CA8	1,289
PGAP2	887

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CA8	P35219	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PGAP2	Q9UHJ9	90.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
GPI anchor biosynthetic process	1	247.8×	0.005	PGAP2
positive regulation of calcium-mediated signaling	1	210.7×	0.005	CA8

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
CA8	0	0
PGAP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CA8	4.2.1.1	carbonic anhydrase

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

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	1	CA8
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PGAP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CA8	0	—
PGAP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.