PMPCA

peptidase, mitochondrial processing subunit alpha, the group of M16 metallopeptidases

Basic information

Region (hg38): 9:136410630-136427992

Previous symbols: [ "INPP5E", "SCAR2", "CLA1" ]

Links

ENSG00000165688 ∙ NCBI:23203 ∙ OMIM:613036 ∙ HGNC:18667 ∙ Uniprot:Q10713 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal recessive spinocerebellar ataxia 2 (Moderate), mode of inheritance: AR
• autosomal recessive spinocerebellar ataxia 2 (Supportive), mode of inheritance: AR
• autosomal recessive spinocerebellar ataxia 2 (Strong), mode of inheritance: AR
• mitochondrial disease (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spinocerebellar ataxia, autosomal recessive 2	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	10528257; 25808372; 26657514

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PMPCA gene.

• not provided (2 variants)
• Autosomal recessive spinocerebellar ataxia 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PMPCA gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				38	2	40
missense		1	79	5	1	86
nonsense		1				1
start loss						0
frameshift	2					2
inframe indel						0
splice donor/acceptor (+/-2bp)	1	1				2
splice region			2	5		7
non coding			2	14	14	30
Total	3	3	81	57	17

Highest pathogenic variant AF is 0.00000657

Variants in PMPCA

This is a list of pathogenic ClinVar variants found in the PMPCA region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
9-136410674-G-T			Likely benign (Aug 02, 2023)
9-136410679-T-A			Uncertain significance (Jun 22, 2023)
9-136410684-C-G		Inborn genetic diseases	Uncertain significance (Apr 26, 2023)
9-136410687-G-A		Inborn genetic diseases	Uncertain significance (Dec 18, 2023)
9-136410688-C-A		PMPCA-related disorder	Benign (Aug 01, 2024)
9-136410689-G-T			Likely benign (Dec 13, 2023)
9-136410717-T-G		Inborn genetic diseases	Uncertain significance (Nov 13, 2023)
9-136410720-T-C			Uncertain significance (Dec 21, 2023)
9-136410732-C-T		Autosomal recessive spinocerebellar ataxia 2	Pathogenic (-)
9-136410742-G-A		Autosomal recessive spinocerebellar ataxia 2	Uncertain significance (Aug 08, 2019)
9-136410750-G-A			Likely benign (Nov 21, 2023)
9-136411878-C-T			Benign (May 22, 2021)
9-136412015-C-T		Autosomal recessive spinocerebellar ataxia 2	Benign (Jan 30, 2024)
9-136412024-TA-T			Pathogenic (Nov 27, 2023)
9-136412039-C-T		PMPCA-related disorder	Likely benign (Mar 01, 2024)
9-136412049-A-T		Inborn genetic diseases	Uncertain significance (Mar 31, 2024)
9-136412050-T-A			Uncertain significance (May 14, 2021)
9-136412051-C-T			Likely benign (Aug 01, 2024)
9-136412061-T-G		Inborn genetic diseases	Uncertain significance (Feb 01, 2023)
9-136412069-A-G		PMPCA-related disorder	Likely benign (Jan 16, 2024)
9-136412071-C-T			Uncertain significance (Apr 21, 2022)
9-136412079-C-T		Inborn genetic diseases	Uncertain significance (Aug 02, 2022)
9-136412085-C-T		Autosomal recessive spinocerebellar ataxia 2	Uncertain significance (Nov 29, 2022)
9-136412089-T-C			Uncertain significance (Dec 11, 2023)
9-136412098-C-T		Inborn genetic diseases	Uncertain significance (Dec 08, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PMPCA	protein_coding	protein_coding	ENST00000371717	13	13104

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.44e-11	0.502	125701	0	47	125748	0.000187

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.162	324	332	0.975	0.0000211	3383
Missense in Polyphen		83	103.24	0.80392		1070
Synonymous	-1.31	164	144	1.14	0.0000104	1070
Loss of Function	1.27	20	27.2	0.736	0.00000157	297

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000327	0.000326
Ashkenazi Jewish	0.00119	0.00119
East Asian	0.000272	0.000272
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000107	0.000105
Middle Eastern	0.000272	0.000272
South Asian	0.000165	0.000163
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Substrate recognition and binding subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins (PubMed:25808372). Most MPP cleavage sites follow an arginine at position -2 (By similarity). {ECO:0000250|UniProtKB:P20069, ECO:0000269|PubMed:25808372}.
• Disease: DISEASE: Spinocerebellar ataxia, autosomal recessive, 2 (SCAR2) [MIM:213200]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR2 is characterized by onset of impaired motor development and ataxic gait in early childhood. Additional features often include loss of fine motor skills, dysarthria, nystagmus, cerebellar signs, and delayed cognitive development with intellectual disability. {ECO:0000269|PubMed:25808372, ECO:0000269|PubMed:26657514}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Metabolism of proteins;3-phosphoinositide degradation;Transport of small molecules;Mitochondrial protein import;Mitochondrial calcium ion transport;Processing of SMDT1 (Consensus)

Recessive Scores

• pRec: 0.107

Intolerance Scores

• loftool: 0.692
• rvis_EVS: -1.18
• rvis_percentile_EVS: 5.97

Haploinsufficiency Scores

• pHI: 0.296
• hipred: N
• hipred_score: 0.476
• ghis: 0.615

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.733

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Pmpca

Gene ontology

• Biological process: proteolysis;protein processing involved in protein targeting to mitochondrion;mitochondrial calcium ion transmembrane transport
• Cellular component: extracellular space;mitochondrion;mitochondrial inner membrane;mitochondrial matrix;mitochondrial processing peptidase complex
• Molecular function: endopeptidase activity;metalloendopeptidase activity;metal ion binding