MTPAP

Chr 10AR

mitochondrial poly(A) polymerase

Also known as: PAPD1, SPAX4, TENT6

NCBI Gene: 55149 ENSG00000107951 UniProt: Q9NVV4 OMIM: 613669

The protein is a polymerase that creates the 3' poly(A) tail of mitochondrial transcripts and is involved in replication-dependent histone mRNA degradation. Mutations cause spastic ataxia 4, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants (pLI 0.999, LOEUF 0.193), suggesting that biallelic variants are required for disease.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the DNA polymerase type-B-like family. This enzyme synthesizes the 3' poly(A) tail of mitochondrial transcripts and plays a role in replication-dependent histone mRNA degradation.[provided by RefSeq, Jan 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Spastic ataxia 4, autosomal recessiveMIM #613672

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · mitochondrial disease · AR · ClinGen 2022

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.19

LOEUF· LoF intol.

—

Mechanism

📖

GeneReview available — MTPAP

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

0.95Z-score

OE missense 0.85 (0.77–0.94)

263 obs / 310.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.19)

0≤0.351.4

Missense OE?0.85 (0.77–0.94)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 1 / 24.6Missense obs/exp: 263 / 310.1Syn Z: -0.63

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

657 rare PASS variants

Rare truncating (LoF)

1 in 5,100

65 rare PASS variants

Rare synonymous (reference)

1 in 160

277 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MTPAP. 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 120	1 in 5,200
South Asian	~43k	1 in 97	1 in 3,100
Remaining (unassigned)	~30k	1 in 96	≈ 1 in 10,000
European (Finnish)	~27k	1 in 490	≈ 1 in 26,000
Admixed American	~22k	1 in 74	1 in 1,600
African / African American	~21k	1 in 100	≈ 1 in 5,500
East Asian	~20k	1 in 120	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 1,200	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 96	none seen

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): 9 of 9 coding exons well covered in gnomAD exomes. Genomes: 8 of 9 (exon 1 below).? see exons ↓