GABRP

Chr 5

gamma-aminobutyric acid type A receptor subunit pi

NCBI Gene: 2568 ENSG00000094755 UniProt: O00591 OMIM: 602729

The pi subunit forms part of GABA-A receptors, heteropentameric chloride channels that mediate inhibitory neurotransmission and are expressed in both neuronal and peripheral tissues including uterus and lungs. Mutations cause autosomal recessive early infantile epileptic encephalopathy, characterized by seizure onset in infancy and developmental impairment. This gene shows very low constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. The subunit encoded by this gene is expressed in several non-neuronal tissues including the uterus and ovaries. This subunit can assemble with known GABA A receptor subunits, and the presence of this subunit alters the sensitivity of recombinant receptors to modulatory agents such as pregnanolone. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.41

Clinical Summary— GABRP

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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

54 VUS of 64 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?

1.41LOEUF

pLI 0.000

Z-score 0.14

OE 0.97 (0.68–1.41)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.16Z-score

OE missense 0.97 (0.87–1.08)

242 obs / 249.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.97 (0.68–1.41)

0≤0.351.4

Missense OE?0.97 (0.87–1.08)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 20 / 20.7Missense obs/exp: 242 / 249.3Syn Z: -0.99

This gene — mechanism propensity

0.78top 25%

GOF

0.80top 10%

LOF

0.2679th %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

64 submitted variants in ClinVar

ClinVar

Classification Summary

VUS54

Likely Benign5

Benign1

VUS

Likely Benign

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	53	54
Likely Benign	0	5	5
Benign	0	1	1
Total	1	59	60

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap GABRP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →