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…

Primary Disease Associations & Inheritance

Spinocerebellar ataxia, autosomal recessive 2MIM #213200

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · mitochondrial disease · AR · ClinGen 2023

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.07

LOEUF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in PMPCA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 73

947 rare PASS variants

Rare truncating (LoF)

1 in 580

139 rare PASS variants

Rare synonymous (reference)

1 in 130

399 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PMPCA. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 92	1 in 560
South Asian	~43k	1 in 68	1 in 1,100
Remaining (unassigned)	~30k	1 in 56	1 in 520
European (Finnish)	~27k	1 in 340	1 in 1,000
Admixed American	~22k	1 in 74	1 in 850
African / African American	~21k	1 in 47	1 in 1,500
East Asian	~20k	1 in 57	1 in 1,600
Ashkenazi Jewish	~13k	1 in 2,100	≈ 1 in 6,100
Middle Eastern	~2,884	1 in 89	1 in 400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 10 of 13 coding exons well covered in gnomAD exomes; exons 1, 3, 4 marginal. Genomes: all 13.? see exons ↓