ENTPD1

Chr 10

ectonucleoside triphosphate diphosphohydrolase 1

Also known as: ATP-DPH, ATPDase, CD39, NTPDase-1, SPG64

NCBI Gene: 953 ENSG00000138185 UniProt: P49961

The encoded protein is a plasma membrane enzyme that hydrolyzes extracellular ATP and ADP to AMP, regulating nucleotide levels and preventing platelet aggregation to support blood flow. Biallelic mutations cause spastic paraplegia 64, an autosomal recessive disorder affecting the motor system. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.602).

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a plasma membrane protein that hydrolyzes extracellular ATP and ADP to AMP. Inhibition of this protein's activity may confer anticancer benefits. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.60

Clinical Summary— ENTPD1

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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)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

18 unique Pathogenic / Likely Pathogenic· 110 VUS of 280 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 — ENTPD1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.60LOEUF

pLI 0.008

Z-score 3.02

OE 0.33 (0.20–0.60)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.83Z-score

OE missense 0.86 (0.77–0.96)

226 obs / 264.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.20–0.60)

0≤0.351.4

Missense OE?0.86 (0.77–0.96)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 8 / 24.0Missense obs/exp: 226 / 264.1Syn Z: 1.09

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongENTPD1-related neurodevelopmental disorder with intellectual disability, hypomyelination, and spastic paraplegiaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7230th %ile

GOF

0.5759th %ile

LOF

0.1994th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

280 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic7

VUS110

Likely Benign93

Benign30

Conflicting11

Pathogenic

Likely Pathogenic

110

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	1	1	0	11
Likely Pathogenic	6	0	1	0	7
VUS	1	97	8	4	110
Likely Benign	0	2	42	49	93
Benign	0	1	27	2	30
Conflicting	—				11
Total	16	101	79	55	262

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap ENTPD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →