ORAI3

Chr 16

ORAI calcium release-activated calcium modulator 3

Also known as: TMEM142C

NCBI Gene: 93129 ENSG00000175938 UniProt: Q9BRQ5 OMIM: 610930

ORAI3 encodes a pore-forming subunit of calcium channels at the plasma membrane, including calcium release-activated calcium (CRAC) channels that mediate calcium influx following endoplasmic reticulum calcium store depletion, and arachidonate-regulated calcium channels that respond to inflammatory metabolites. The gene is relatively tolerant to loss-of-function variants (pLI = 0.03, LOEUF = 1.23), and no definitive disease associations have been established in the provided data. ORAI3 plays important roles in T cell immune responses and calcium signaling dynamics.

OMIM ResearchSummary from RefSeq, UniProt

Enables store-operated calcium channel activity. Involved in store-operated calcium entry. Located in plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.23

Clinical Summary— ORAI3

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Population Constraint (gnomAD)

Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.23LOEUF

pLI 0.034

Z-score 1.20

OE 0.48 (0.22–1.23)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.07Z-score

OE missense 0.98 (0.86–1.12)

160 obs / 162.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.48 (0.22–1.23)

0≤0.351.4

Missense OE?0.98 (0.86–1.12)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 3 / 6.3Missense obs/exp: 160 / 162.7Syn Z: -0.37

This gene — mechanism propensity

0.76top 25%

GOF

0.76top 25%

LOF

0.3067th %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.