PNPT1

Chr 2ARAD

polyribonucleotide nucleotidyltransferase 1

Also known as: COXPD13, DFNB70, OLD35, PNPASE, SCA25, old-35

NCBI Gene: 87178ENSG00000138035UniProt: Q8TCS8

The protein encoded by this gene belongs to the evolutionary conserved polynucleotide phosphorylase family comprised of phosphate dependent 3'-to-5' exoribonucleases implicated in RNA processing and degradation. This enzyme is predominantly localized in the mitochondrial intermembrane space and is involved in import of RNA to mitochondria. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency-13 and autosomal recessive nonsyndromic deafness-70. Related pseudogenes are found on chromosomes 3 and 7. [provided by RefSeq, Dec 2012]

Primary Disease Associations & Inheritance

Combined oxidative phosphorylation deficiency 13MIM #614932
AR
Deafness, autosomal recessive 70, with or without adult-onset neurodegenerationMIM #614934
AR
Spinocerebellar ataxia 25MIM #608703
AD
1035
ClinVar variants
42
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PNPT1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.
📋
ClinVar Variants
42 Pathogenic / Likely Pathogenic· 187 VUS of 1035 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.47LOEUF
pLI 0.000
Z-score 4.56
OE 0.31 (0.21–0.47)
Moderately constrained

More LoF-intolerant than ~75% 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.
0.42Z-score
OE missense 0.94 (0.86–1.02)
385 obs / 409.1 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.0.31 (0.21–0.47)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.86–1.02)
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.1.12
0≤1.21.6
LoF obs/exp: 16 / 51.2Missense obs/exp: 385 / 409.1Syn Z: -1.18

ClinVar Variant Classifications

1035 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic23
VUS187
Likely Benign233
Benign8
19
Pathogenic
23
Likely Pathogenic
187
VUS
233
Likely Benign
8
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
0
10
0
19
Likely Pathogenic
17
1
5
0
23
VUS
3
159
22
3
187
Likely Benign
1
1
144
87
233
Benign
0
0
8
0
8
Total3016118990470

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

View in ClinVar →

Protein Context — Lollipop Plot

PNPT1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

PNPT1-related hearing loss

definitive
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

PNPT1-related respiratory chain disorder

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Combined oxidative phosphorylation deficiency 13

MIM #614932

Molecular basis of disorder known

Autosomal recessive

Deafness, autosomal recessive 70, with or without adult-onset neurodegeneration

MIM #614934

Molecular basis of disorder known

Autosomal recessive

Spinocerebellar ataxia 25

MIM #608703

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Autosomal dominant cerebellar ataxias: new genes and progress towards treatments.
Coarelli G et al.·Lancet Neurol
2023Review
Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
López-Polo V et al.·Nat Commun
2024
PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic heterogeneity among hearing impaired assortative mating families in Southern India.
Vanniya S P et al.·Ann Hum Genet
2022
Polyribonucleotide phosphorylase is overexpressed in hepatocellular cancer, promoting epithelial phenotype maintenance and tumor progression.
Revert-Ros F et al.·Pathol Res Pract
2024
Childhood-Onset Hereditary Spastic Paraplegia (HSP): A Case Series and Review of Literature.
Panwala TF et al.·Pediatr Neurol
2022Review
cGAS/STING-Independent Induction of Type I Interferon by Inhibitors of the Histone Methylase KDM5B.
Montano MM et al.·FASEB J
2025
Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25.
Barbier M et al.·Ann Neurol
2022
Clinical Value of Circ-PNPT1 on Adverse Pregnancy Outcomes of Patients with Gestational Diabetes Mellitus.
Wang S et al.·Endocr Metab Immune Disord Drug Targets
2024Cohort
PNPT1 mutations may cause Aicardi-Goutières-Syndrome.
Bamborschke D et al.·Brain Dev
2021Case report
A Novel Pathogenic Variant in the SCA25-Related Gene Expanding the Etiology of Early-Onset and Progressive Cerebellar Ataxia in Childhood.
Ferrera G et al.·Neuropediatrics
2024Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
A Preliminary Study of circ-PNPT1/miR-144-3p/UBE2G1 Expression in Placental Tissues and Serum and Its Mechanism in Patients With Gestational Diabetes Mellitus.
Wang J et al.·Mol Reprod Dev
2025Cohort
A novel polyribonucleotide nucleotidyltransferase 1 (PNPT1) gene variant potentially associated with combined oxidative phosphorylation deficiency 13: case report and literature review.
Li YY et al.·Transl Pediatr
2025🔓 Open AccessReview
Heterozygous PNPT1 Variants Cause a Sensory Ataxic Neuropathy.
Haddad S et al.·Eur J Neurol
2025🔓 Open Access
Unravelling Heterogeneity: A Rare PNPT1 Variant in Childhood-Onset Spinocerebellar Ataxia with Sensorineural Hearing Loss.
Nallapaneni LM et al.·Cerebellum
2024
Blockade of pan-viral propagation by inhibition of host cell PNPT1.
Qu S et al.·Int J Antimicrob Agents
2024
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