GLRA3

Chr 4

glycine receptor alpha 3

NCBI Gene: 8001ENSG00000145451UniProt: O75311

The protein functions as a ligand-gated chloride channel that responds to extracellular glycine and plays an important role in down-regulating neuronal excitability and generating inhibitory postsynaptic currents. Mutations cause autosomal recessive hyperekplexia, a neurological disorder characterized by exaggerated startle responses and muscle stiffness. The gene shows low constraint to loss-of-function variants (pLI ~0), suggesting that biallelic variants are required for disease manifestation.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
2
Pubs (1 yr)
69
P/LP submissions
0%
P/LP missense
0.70
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— GLRA3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
69 unique Pathogenic / Likely Pathogenic· 64 VUS of 141 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
0.70LOEUF
pLI 0.000
Z-score 2.83
OE 0.44 (0.28–0.70)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.98Z-score
OE missense 0.83 (0.74–0.93)
212 obs / 256.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.44 (0.28–0.70)
0≤0.351.4
Missense OE0.83 (0.74–0.93)
0≤0.61.4
Synonymous OE1.06
0≤1.21.6
LoF obs/exp: 13 / 29.6Missense obs/exp: 212 / 256.4Syn Z: -0.46
DN
0.85top 5%
GOF
0.82top 10%
LOF
0.1894th %ile

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

DNprediction above median
GOFprediction 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

141 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic67
Likely Pathogenic2
VUS64
Benign1
67
Pathogenic
2
Likely Pathogenic
64
VUS
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
67
0
67
Likely Pathogenic
0
0
2
0
2
VUS
0
50
14
0
64
Likely Benign
0
0
0
0
0
Benign
0
0
0
1
1
Total050831134

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

View in ClinVar →

Protein Context — Lollipop Plot

GLRA3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
A Glra3 phosphodeficient mouse mutant establishes the critical role of protein kinase A-dependent phosphorylation and inhibition of glycine receptors in spinal inflammatory hyperalgesia.
Werynska K et al.·Pain
2021Open AccessFunctional
Hippocampal Characteristics and Invariant Sequence Elements Distribution of GLRA2 and GLRA3 C-to-U Editing.
Schaefermeier P et al.·Mol Syndromol
2017
A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R.
Ramanathan S et al.·BMC Med Genet
2004Open Access
Genetic variation of the human glycine receptor subunit genes GLRA3 and GLRB and susceptibility to idiopathic generalized epilepsies.
Sobetzko D et al.·Am J Med Genet
2001
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients