P2RX6

Chr 22

purinergic receptor P2X 6

Also known as: P2RXL1, P2X6, P2XM

NCBI Gene: 9127 ENSG00000099957 UniProt: O15547 OMIM: 608077

The P2RX6 protein functions as a modulatory subunit of ATP-gated ion channels, requiring P2RX4 or P2RX2 for plasma membrane localization and forming functional heterotrimeric receptors, and can translocate to the nucleus to regulate post-transcriptional modifications in neurons. This gene is not highly constrained against loss-of-function variants and currently has no established disease associations in humans. Clinical significance of P2RX6 variants remains to be determined.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene belongs to the family of P2X receptors, which are ATP-gated ion channels and mediate rapid and selective permeability to cations. This gene is predominantly expressed in skeletal muscle, and regulated by p53. The encoded protein is associated with VE-cadherin at the adherens junctions of human umbilical vein endothelial cells. Alternative splicing results in multiple transcript variants. A related pseudogene, which is also located on chromosome 22, has been identified. [provided by RefSeq, Apr 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.10

Clinical Summary— P2RX6

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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

61 VUS of 73 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?

1.10LOEUF

pLI 0.000

Z-score 1.20

OE 0.72 (0.49–1.10)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.84Z-score

OE missense 0.85 (0.76–0.95)

212 obs / 249.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.72 (0.49–1.10)

0≤0.351.4

Missense OE?0.85 (0.76–0.95)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 16 / 22.1Missense obs/exp: 212 / 249.3Syn Z: -0.18

This gene — mechanism propensity

0.6937th %ile

GOF

0.75top 25%

LOF

0.2190th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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

73 submitted variants in ClinVar

ClinVar

Classification Summary

VUS61

Likely Benign7

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	1	60	61
Likely Benign	0	7	7
Benign	0	0	0
Total	1	67	68

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

View in ClinVar →

359 pathogenic / likely-pathogenic (of 422) ClinVar copy-number / structural variants overlap P2RX6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →