PITRM1

Chr 10AR

pitrilysin metallopeptidase 1

Also known as: MP1, PreP, SCAR30

NCBI Gene: 10531 ENSG00000107959 UniProt: Q5JRX3 OMIM: 618211

This gene encodes a mitochondrial matrix metalloendopeptidase that degrades transit peptides after mitochondrial protein import and can also degrade amyloid-beta peptides that accumulate in mitochondria. Mutations cause spinocerebellar ataxia, autosomal recessive 30, which follows autosomal recessive inheritance. The gene is not highly constrained against loss-of-function variants (pLI near zero), consistent with the recessive inheritance pattern of the associated ataxia.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is an ATP-dependent metalloprotease that degrades post-cleavage mitochondrial transit peptides. The encoded protein binds zinc and can also degrade amyloid beta A4 protein, suggesting a possible role in Alzheimer's disease. [provided by RefSeq, Dec 2016]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Spinocerebellar ataxia, autosomal recessive 30MIM #619405

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Spinocerebellar ataxia, autosomal recessive 30; no ClinGen or GenCC tier

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.94

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.94LOEUF

pLI 0.000

Z-score 1.93

OE 0.72 (0.56–0.94)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.84Z-score

OE missense 1.10 (1.03–1.17)

653 obs / 595.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.72 (0.56–0.94)

0≤0.351.4

Missense OE?1.10 (1.03–1.17)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 40 / 55.5Missense obs/exp: 653 / 595.5Syn Z: -2.68

Background carrier burden — how many people carry a rare variant somewhere in PITRM1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 22

1,808 rare PASS variants

Rare truncating (LoF)

1 in 340

316 rare PASS variants

Rare synonymous (reference)

1 in 46

657 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PITRM1. 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 31	1 in 350
South Asian	~43k	1 in 24	1 in 250
Remaining (unassigned)	~30k	1 in 19	1 in 430
European (Finnish)	~27k	1 in 91	1 in 1,600
Admixed American	~22k	1 in 17	1 in 530
African / African American	~21k	1 in 23	1 in 320
East Asian	~20k	1 in 23	1 in 150
Ashkenazi Jewish	~13k	1 in 99	1 in 1,600
Middle Eastern	~2,884	1 in 23	≈ 1 in 960

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): 18 of 27 coding exons well covered in gnomAD exomes; exons 3, 4, 5, 9, 11 and 4 more marginal. Genomes: 26 of 27 (exon 4 below).? see exons ↓