NUDT1

Chr 7

nudix hydrolase 1

Also known as: MTH1

NCBI Gene: 4521 ENSG00000106268 UniProt: P36639 OMIM: 600312

The protein hydrolyzes oxidized purine nucleoside triphosphates to prevent their incorporation into DNA and RNA, thereby protecting cells from oxidative damage and mutagenic transversions. Mutations cause autosomal recessive developmental delay, intellectual disability, seizures, and movement disorders with early childhood onset. This gene is not highly constrained against loss-of-function variation and has an associated GeneReviews entry for detailed clinical guidance.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

Misincorporation of oxidized nucleoside triphosphates into DNA/RNA during replication and transcription can cause mutations that may result in carcinogenesis or neurodegeneration. The protein encoded by this gene is an enzyme that hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP, 8-oxo-dATP, 2-hydroxy-dATP, and 2-hydroxy rATP, to monophosphates, thereby preventing misincorporation. The encoded protein is localized mainly in the cytoplasm, with some in the mitochondria, suggesting that it is involved in the sanitization of nucleotide pools both for nuclear and mitochondrial genomes. Several alternatively spliced transcript variants, some of which encode distinct isoforms, have been identified. Additional variants have been observed, but their full-length natures have not been determined. A rare single-nucleotide polymorphism that results in the production of an additional, longer isoform (p26) has been described. [provided by RefSeq, Dec 2018]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.94

Clinical Summary— NUDT1

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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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ClinVar Variants

28 VUS of 37 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NUDT1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.94LOEUF

pLI 0.000

Z-score -1.63

OE 1.59 (1.01–1.94)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.61Z-score

OE missense 1.16 (1.01–1.35)

127 obs / 109.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.59 (1.01–1.94)

0≤0.351.4

Missense OE?1.16 (1.01–1.35)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 14 / 8.8Missense obs/exp: 127 / 109.1Syn Z: -0.45

This gene — mechanism propensity

0.6355th %ile

GOF

0.5759th %ile

LOF

0.3453th %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.

ClinVar Variant Classifications

37 submitted variants in ClinVar

ClinVar

Classification Summary

VUS28

Likely Benign3

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	28	0	28
Likely Benign	2	1	3
Benign	0	0	0
Total	30	1	31

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

View in ClinVar →

36 pathogenic / likely-pathogenic (of 55) ClinVar copy-number / structural variants overlap NUDT1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →