PIEZO1

Chr 16ARAD

piezo type mechanosensitive ion channel component 1 (Er blood group)

Also known as: DHS, ER, FAM38A, LMPH3, LMPHM6, Mib

NCBI Gene: 9780 ENSG00000103335 UniProt: Q92508

The protein encoded by this gene is a mechanically-activated ion channel that links mechanical forces to biological signals. The encoded protein contains 36 transmembrane domains and functions as a homotetramer. Defects in this gene have been associated with dehydrated hereditary stomatocytosis. [provided by RefSeq, Jul 2015]

Primary Disease Associations & Inheritance

[ER blood group system]MIM #620207

Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edemaMIM #194380

Lymphatic malformation 6MIM #616843

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

-3.4

Missense Z

0.58

LOEUF

Clinical Summary— PIEZO1

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Gene-Disease Validity (ClinGen)

dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema · ADStrong

Strong evidence — appropriate for clinical testing

2 total gene-disease associations curated

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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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Clinical Trials

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.58LOEUF

pLI 0.000

Z-score 5.40

OE 0.46 (0.37–0.58)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-3.43Z-score

OE missense 1.25 (1.20–1.29)

1905 obs / 1527.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.46 (0.37–0.58)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.25 (1.20–1.29)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.59

0≤1.21.6

LoF obs/exp: 55 / 118.4Missense obs/exp: 1905 / 1527.4Syn Z: -12.05

0.73top 25%

GOF

0.83top 10%

LOF

0.2483th %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 · 1 literature citation

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNExpressing these dominant negative PIEZO1 variants in zebrafish endothelium leads to defective aortic valve development.PMID:32251670

GOFGain-of-function mutations in the human PIEZO1 gene cause the autosomal dominant hemolytic anemia, hereditary xerocytosis (also known as dehydrated stomatocytosis).PMID:28728825

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