NT5C2

Chr 10AR

5'-nucleotidase, cytosolic II

Also known as: GMP, NT5B, PNT5, SPG45, SPG65, cN-II

NCBI Gene: 22978ENSG00000076685UniProt: P49902

This gene encodes a hydrolase that serves as an important role in cellular purine metabolism by acting primarily on inosine 5'-monophosphate and other purine nucleotides. [provided by RefSeq, Oct 2011]

Primary Disease Associations & Inheritance

Spastic paraplegia 45, autosomal recessiveMIM #613162
AR
204
ClinVar variants
38
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NT5C2
🧬
Gene-Disease Validity (ClinGen)
complex hereditary spastic paraplegia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
38 Pathogenic / Likely Pathogenic· 70 VUS of 204 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.70LOEUF
pLI 0.000
Z-score 2.88
OE 0.46 (0.30–0.70)
Tolerant

Typical tolerance to LoF variation

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.
2.64Z-score
OE missense 0.58 (0.51–0.66)
181 obs / 312.5 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.46 (0.30–0.70)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.58 (0.51–0.66)
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.1.09
0≤1.21.6
LoF obs/exp: 15 / 32.8Missense obs/exp: 181 / 312.5Syn Z: -0.76

ClinVar Variant Classifications

204 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32
Likely Pathogenic6
VUS70
Likely Benign75
Benign19
Conflicting2
32
Pathogenic
6
Likely Pathogenic
70
VUS
75
Likely Benign
19
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
1
20
0
32
Likely Pathogenic
2
2
2
0
6
VUS
3
55
12
0
70
Likely Benign
0
0
41
34
75
Benign
0
1
17
1
19
Conflicting
—2
Total16599235204

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

View in ClinVar →

Protein Context — Lollipop Plot

NT5C2 · 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 paraplegia 45, autosomal recessive

MIM #613162

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
An Alternatively Spliced Gain-of-Function NT5C2 Isoform Contributes to Chemoresistance in Acute Lymphoblastic Leukemia.
Torres-Diz M et al.·Cancer Res
2024
Expanding the clinical relevance of the 5'-nucleotidase cN-II/NT5C2.
Jordheim LP·Purinergic Signal
2018Review
Multiomic Underpinnings of Drug Targets for Intracranial Aneurysm: Evidence From Diversified Mendelian Randomization.
Fan YX et al.·CNS Neurosci Ther
2025
NUDT15 polymorphism and NT5C2 and PRPS1 mutations influence thiopurine sensitivity in acute lymphoblastic leukaemia cells.
Somazu S et al.·J Cell Mol Med
2021
Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia.
Tzoneva G et al.·Nature
2018Functional
Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia.
Jiang C et al.·Clin Pharmacol Ther
2021
[NT5C2 expression in children with acute leukemia and its clinical significance].
Wang Y et al.·Zhonghua Xue Ye Xue Za Zhi
2015
CRISPR/Cas9-Mediated Induction of Relapse-Specific NT5C2 and PRPS1 Mutations Confers Thiopurine Resistance as a Relapsed Lymphoid Leukemia Model.
Nguyen TTT et al.·Mol Pharmacol
2023Functional
Subclonal NT5C2 mutations are associated with poor outcomes after relapse of pediatric acute lymphoblastic leukemia.
Barz MJ et al.·Blood
2020
Molecular Profiling Reveals Novel Gene Fusions and Genetic Markers for Refined Patient Stratification in Pediatric Acute Lymphoblastic Leukemia.
Péterffy B et al.·Mod Pathol
2025
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