GRINA

Chr 8

glutamate ionotropic receptor NMDA type subunit associated protein 1

Also known as: HNRGW, LFG1, NMDARA1, TMBIM3

NCBI Gene: 2907 ENSG00000178719 UniProt: Q7Z429 OMIM: 138251

The protein functions as a calcium channel and potential apoptotic regulator involved in endoplasmic reticulum calcium homeostasis and negative regulation of neuronal apoptosis. Mutations cause autosomal recessive developmental and epileptic encephalopathy with intellectual disability. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.49), suggesting some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable calcium channel activity. Predicted to be involved in apoptotic signaling pathway; negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; and negative regulation of neuron apoptotic process. Predicted to act upstream of or within endoplasmic reticulum calcium ion homeostasis and negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway. Located in Golgi membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.49

Clinical Summary— GRINA

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.49LOEUF

pLI 0.442

Z-score 3.13

OE 0.22 (0.10–0.49)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.21Z-score

OE missense 0.76 (0.67–0.87)

153 obs / 201.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.10–0.49)

0≤0.351.4

Missense OE?0.76 (0.67–0.87)

0≤0.61.4

Synonymous OE?1.27

0≤1.21.6

LoF obs/exp: 4 / 18.6Missense obs/exp: 153 / 201.3Syn Z: -2.04

This gene — mechanism propensity

0.77top 25%

GOF

0.79top 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.