PMPCA

Chr 9AR

peptidase, mitochondrial processing subunit alpha

Also known as: Alpha-MPP, CLA1, CPD3, INPP5E, MAS2, P-55, SCAR2

NCBI Gene: 23203 ENSG00000165688 UniProt: Q10713 OMIM: 613036

The protein functions as the substrate recognition and binding subunit of the mitochondrial processing protease, which cleaves transit peptides from newly imported nuclear-encoded mitochondrial proteins. Mutations cause spinocerebellar ataxia, autosomal recessive 2, which primarily affects cerebellar function leading to progressive ataxia. The gene follows autosomal recessive inheritance and is highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is found in the mitochondrion, where it represents the alpha subunit of a proteolytic heterodimer. This heterodimer is responsible for cleaving the transit peptide from nuclear-encoded mitochondrial proteins. Defects in this gene are a cause of spinocerebellar ataxia, autosomal recessive 2. [provided by RefSeq, Mar 2016]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 1.071 OMIM phenotype

Clinical Summary— PMPCA

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 146 VUS of 290 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.07LOEUF

pLI 0.000

Z-score 1.27

OE 0.74 (0.52–1.07)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.16Z-score

OE missense 0.97 (0.89–1.07)

324 obs / 332.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.74 (0.52–1.07)

0≤0.351.4

Missense OE?0.97 (0.89–1.07)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 20 / 27.2Missense obs/exp: 324 / 332.3Syn Z: -1.31

This gene — mechanism propensity

0.6258th %ile

GOF

0.5268th %ile

LOF

0.3939th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

290 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic3

VUS146

Likely Benign90

Benign21

Conflicting7

Pathogenic

Likely Pathogenic

146

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	6	1	0	11
Likely Pathogenic	3	0	0	0	3
VUS	0	141	5	0	146
Likely Benign	0	4	31	55	90
Benign	0	1	17	3	21
Conflicting	—				7
Total	7	152	54	58	278

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

77 pathogenic / likely-pathogenic (of 95) ClinVar copy-number / structural variants overlap PMPCA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →