MTPAP

Chr 10AR

mitochondrial poly(A) polymerase

NCBI Gene: 55149ENSG00000107951UniProt: Q9NVV4

Polymerase that creates the 3' poly(A) tail of mitochondrial transcripts. Can use all four nucleotides, but has higher activity with ATP and UTP (in vitro). Plays a role in replication-dependent histone mRNA degradation. May be involved in the terminal uridylation of mature histone mRNAs before their degradation is initiated. Might be responsible for the creation of some UAA stop codons which are not encoded in mtDNA

Primary Disease Associations & Inheritance

?Spastic ataxia 4, autosomal recessiveMIM #613672
AR
463
ClinVar variants
13
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— MTPAP
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
13 Pathogenic / Likely Pathogenic· 198 VUS of 463 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.19LOEUF
pLI 0.999
Z-score 4.40
OE 0.04 (0.01–0.19)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.95Z-score
OE missense 0.85 (0.77–0.94)
263 obs / 310.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.04 (0.01–0.19)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.77–0.94)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.07
0≤1.21.6
LoF obs/exp: 1 / 24.6Missense obs/exp: 263 / 310.1Syn Z: -0.63

ClinVar Variant Classifications

463 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic2
VUS198
Likely Benign179
Benign50
Conflicting12
11
Pathogenic
2
Likely Pathogenic
198
VUS
179
Likely Benign
50
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
10
0
11
Likely Pathogenic
0
1
1
0
2
VUS
5
173
18
2
198
Likely Benign
0
6
86
87
179
Benign
0
2
44
4
50
Conflicting
—12
Total518315993452

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

View in ClinVar →

Protein Context — Lollipop Plot

MTPAP · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Spastic ataxia 4, autosomal recessive

MIM #613672

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A human mitochondrial poly(A) polymerase mutation reveals the complexities of post-transcriptional mitochondrial gene expression.
Wilson WC et al.·Hum Mol Genet
2014
Clinical and molecular assessment of a spastic ataxia 4 (SPAX4) patient with a novel variant in the MTPAP gene, and a systematic review.
Ravanbod M et al.·Gene
2025Case report
Homozygous mutation of MTPAP causes cellular radiosensitivity and persistent DNA double-strand breaks.
Martin NT et al.·Cell Death Dis
2014
Biallelic Mutations in MTPAP Associated with a Lethal Encephalopathy.
Van Eyck L et al.·Neuropediatrics
2020Case report
A Case Report of Primary Ovarian Failure in an Adolescent Associated With a Homozygous Pathogenic Variant in the Mitochondrial Poly-A-Polymerase Gene (MTPAP).
Epstein J et al.·J Pediatr Adolesc Gynecol
2025Case report
Structure of mitochondrial poly(A) RNA polymerase reveals the structural basis for dimerization, ATP selectivity and the SPAX4 disease phenotype.
Lapkouski M et al.·Nucleic Acids Res
2015
Complex hereditary peripheral neuropathies caused by novel variants in mitochondrial-related nuclear genes.
Hiramatsu Y et al.·J Neurol
2022
Defective mitochondrial mRNA maturation is associated with spastic ataxia.
Crosby AH et al.·Am J Hum Genet
2010
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools