Autosomal recessive spinocerebellar ataxia 2

Summary

Autosomal recessive spinocerebellar ataxia 2 (MONDO:0008943) is a disease caused by PMPCA (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: PMPCA (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 25
• Phenotypes (HPO): 29

Clinical features

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0000640	Gaze-evoked nystagmus	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001310	Dysmetria	Very frequent (80-99%)
HP:0002066	Gait ataxia	Very frequent (80-99%)
HP:0031936	Delayed ability to walk	Very frequent (80-99%)
HP:0000657	Oculomotor apraxia	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001348	Brisk reflexes	Frequent (30-79%)
HP:0001763	Pes planus	Frequent (30-79%)
HP:0002275	Poor motor coordination	Frequent (30-79%)
HP:0002506	Diffuse cerebral atrophy	Frequent (30-79%)
HP:0006855	Cerebellar vermis atrophy	Frequent (30-79%)
HP:0007272	Progressive psychomotor deterioration	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000602	Ophthalmoplegia	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0002198	Dilated fourth ventricle	Occasional (5-29%)
HP:0002280	Enlarged cisterna magna	Occasional (5-29%)
HP:0003128	Lactic acidosis	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0010794	Impaired visuospatial constructive cognition	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive spinocerebellar ataxia 2
Mondo ID	MONDO:0008943
MeSH	C565865
OMIM	213200
Orphanet	1170
DOID	DOID:0080061
SNOMED CT	715369006
UMLS	C1859298
MedGen	349134
GARD	0001199
Is cancer (heuristic)	no

Also known as: autosomal recessive congenital cerebellar ataxia caused by mutation in PMPCA · autosomal recessive spinocerebellar ataxia type 2 · cerebellar granular cell hypoplasia and mental retardation, congenital · CPD3 · CPDIII · PMPCA autosomal recessive congenital cerebellar ataxia · SCAR2 · spinocerebellar ataxia, autosomal recessive 2

Data availability: 25 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 › autosomal genetic disease › autosomal recessive disease › autosomal recessive cerebellar ataxia › autosomal recessive congenital cerebellar ataxia › autosomal recessive spinocerebellar ataxia 2

Related subtypes (6): cerebellar ataxia, intellectual disability, and dysequilibrium, Cayman type cerebellar ataxia, autosomal recessive spinocerebellar ataxia 17, Joubert syndrome and related disorders, CAMOS syndrome, congenital cerebellar ataxia due to RNU12 mutation

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

25 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 6 pathogenic, 4 conflicting classifications of pathogenicity, 2 benign, 1 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
375401	NM_015160.3(PMPCA):c.554G>A (p.Arg185Gln)	LOC126860792	Pathogenic	no assertion criteria provided
375400	NM_015160.3(PMPCA):c.64C>T (p.Arg22Trp)	LOC130003010	Pathogenic	no assertion criteria provided
1256053	NM_015160.3(PMPCA):c.1408+1G>A	PMPCA	Pathogenic	criteria provided, single submitter
221552	NM_015160.3(PMPCA):c.1129G>A (p.Ala377Thr)	PMPCA	Pathogenic	no assertion criteria provided
221564	NM_015160.3(PMPCA):c.287C>T (p.Ser96Leu)	PMPCA	Pathogenic	no assertion criteria provided
221565	NM_015160.3(PMPCA):c.1543G>A (p.Gly515Arg)	PMPCA	Pathogenic	no assertion criteria provided
2572590	NM_015160.3(PMPCA):c.1204C>T (p.Arg402Ter)	PMPCA	Likely pathogenic	criteria provided, single submitter
2572476	NM_015160.3(PMPCA):c.667C>T (p.Arg223Cys)	LOC126860792	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033742	NM_015160.3(PMPCA):c.897+6G>A	PMPCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2978278	NM_015160.3(PMPCA):c.898-2A>G	PMPCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3363497	NM_015160.3(PMPCA):c.737dup (p.Tyr246Ter)	PMPCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027948	NM_015160.3(PMPCA):c.803G>A (p.Arg268Gln)	LOC126860792	Uncertain significance	criteria provided, multiple submitters, no conflicts
1256054	NM_015160.3(PMPCA):c.634-266T>G	LOC126860792	Uncertain significance	criteria provided, single submitter
221566	NM_015160.3(PMPCA):c.766G>A (p.Val256Met)	LOC126860792	Uncertain significance	criteria provided, single submitter
3065168	NM_015160.3(PMPCA):c.802C>T (p.Arg268Trp)	LOC126860792	Uncertain significance	criteria provided, single submitter
2435095	NM_015160.3(PMPCA):c.71+3G>A	LOC130003010	Uncertain significance	criteria provided, single submitter
1027947	NM_015160.3(PMPCA):c.485C>T (p.Thr162Met)	PMPCA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033740	NM_015160.3(PMPCA):c.1205G>C (p.Arg402Pro)	PMPCA	Uncertain significance	criteria provided, single submitter
1033741	NM_015160.3(PMPCA):c.258G>C (p.Gln86His)	PMPCA	Uncertain significance	criteria provided, multiple submitters, no conflicts
1802623	NM_015160.3(PMPCA):c.160C>T (p.Pro54Ser)	PMPCA	Uncertain significance	criteria provided, single submitter
2435094	NM_015160.3(PMPCA):c.1099G>A (p.Val367Met)	PMPCA	Uncertain significance	criteria provided, multiple submitters, no conflicts
3236231	NM_015160.3(PMPCA):c.1330G>A (p.Val444Met)	PMPCA	Uncertain significance	criteria provided, single submitter
1598832	NM_015160.3(PMPCA):c.633+17G>A	LOC126860792	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1220620	NM_015160.3(PMPCA):c.90C>T (p.Tyr30=)	PMPCA	Benign	criteria provided, multiple submitters, no conflicts
1295437	NM_015160.3(PMPCA):c.1200+33G>A	PMPCA	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · 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
PMPCA	Strong	Autosomal recessive	autosomal recessive spinocerebellar ataxia 2	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PMPCA	Orphanet:1170	Autosomal recessive cerebelloparenchymal disorder type 3

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
PMPCA	HGNC:18667	ENSG00000165688	Q10713	Mitochondrial-processing peptidase subunit alpha	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PMPCA	Mitochondrial-processing peptidase subunit alpha	Substrate recognition and binding subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins.

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PMPCA	Protease	yes	3.4.24.64	Pept_M16_Zn_BS, Peptidase_M16_C, Metalloenz_LuxS/M16

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
adrenal tissue	1
apex of heart	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PMPCA	276	ubiquitous	marker	right lobe of liver, adrenal tissue, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PMPCA	3,679

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PMPCA	Q10713	88.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Processing of SMDT1	1	634.4×	0.006	PMPCA
Mitochondrial calcium ion transport	1	543.8×	0.006	PMPCA
Protein localization	1	190.3×	0.010	PMPCA
Mitochondrial protein import	1	167.9×	0.010	PMPCA
Mitochondrial protein degradation	1	114.2×	0.012	PMPCA
Transport of small molecules	1	25.1×	0.046	PMPCA
Metabolism of proteins	1	12.4×	0.081	PMPCA

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
obsolete protein processing involved in protein targeting to mitochondrion	1	2106.5×	9e-04	PMPCA
protein processing	1	170.2×	0.006	PMPCA

Therapeutics

Drug target analysis

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

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
PMPCA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PMPCA	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PMPCA	3.4.24.64	mitochondrial processing peptidase

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	1	PMPCA
E	Difficult family or no structure, no drug	0

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)
PMPCA	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.