NT5C2

Chr 10AR

5'-nucleotidase, cytosolic II

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

NCBI Gene: 22978 ENSG00000076685 UniProt: P49902 OMIM: 600417

The protein encoded by this gene is a cytosolic 5'-nucleotidase that dephosphorylates purine nucleoside monophosphates, particularly IMP and GMP, and also functions as a phosphotransferase to regulate cellular purine nucleotide pools. Mutations cause spastic paraplegia 45, an autosomal recessive disorder. The pathogenic mechanism likely involves disruption of purine metabolism leading to spasticity and progressive weakness of the lower limbs.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.701 OMIM phenotype

Clinical Summary— NT5C2

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Gene-Disease Validity (ClinGen)

complex hereditary spastic paraplegia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.70LOEUF

pLI 0.000

Z-score 2.88

OE 0.46 (0.30–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

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?

LoF OE?0.46 (0.30–0.70)

0≤0.351.4

Missense OE?0.58 (0.51–0.66)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 15 / 32.8Missense obs/exp: 181 / 312.5Syn Z: -0.76

This gene — mechanism propensity

0.6454th %ile

GOF

0.6149th %ile

LOF

0.2678th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.