ENPP6

Chr 4

ectonucleotide pyrophosphatase/phosphodiesterase 6

Also known as: NPP6

NCBI Gene: 133121 ENSG00000164303 UniProt: Q6UWR7 OMIM: 616983

The ENPP6 protein is a choline-specific glycerophosphodiesterase that hydrolyzes glycerophosphocholine and lysophosphatidylcholine to supply choline to cells. Mutations cause neurodevelopmental disorders with intellectual disability and hypotonia, inherited in an autosomal recessive pattern. This gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

Enables glycerophosphocholine cholinephosphodiesterase activity. Involved in choline metabolic process and lipid metabolic process. Located in extracellular region and plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.18

Clinical Summary— ENPP6

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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

79 VUS of 85 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.18LOEUF

pLI 0.000

Z-score 0.96

OE 0.77 (0.51–1.18)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.31Z-score

OE missense 0.95 (0.85–1.05)

256 obs / 270.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.77 (0.51–1.18)

0≤0.351.4

Missense OE?0.95 (0.85–1.05)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 15 / 19.6Missense obs/exp: 256 / 270.4Syn Z: -0.84

This gene — mechanism propensity

0.7130th %ile

GOF

0.5563th %ile

LOF

0.2872th %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

85 submitted variants in ClinVar

ClinVar

Classification Summary

VUS79

Likely Benign1

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	78	0	0	79
Likely Benign	0	0	0	1	1
Benign	0	0	1	1	2
Total	1	78	1	2	82

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

View in ClinVar →

103 pathogenic / likely-pathogenic (of 116) ClinVar copy-number / structural variants overlap ENPP6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →