GLRA2

Chr XX-linked

glycine receptor alpha 2

Also known as: GLR, MRXSP

NCBI Gene: 2742 ENSG00000101958 UniProt: P23416 OMIM: 305990

The protein is an alpha subunit of heteromeric glycine-gated chloride channels that contributes to inhibitory postsynaptic currents and down-regulation of neuronal excitability. Mutations cause X-linked syndromic intellectual developmental disorder, Pilorge type. This gene shows X-linked inheritance and is highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The glycine receptor consists of two subunits, alpha and beta, and acts as a pentamer. The protein encoded by this gene is an alpha subunit and can bind strychnine. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismX-linkedLOEUF 0.301 OMIM phenotype

Clinical Summary— GLRA2

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

11 unique Pathogenic / Likely Pathogenic· 62 VUS of 139 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.30LOEUF

pLI 0.973

Z-score 3.42

OE 0.06 (0.02–0.30)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.70Z-score

OE missense 0.43 (0.36–0.52)

78 obs / 179.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.30)

0≤0.351.4

Missense OE?0.43 (0.36–0.52)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 1 / 15.6Missense obs/exp: 78 / 179.9Syn Z: 0.26

This gene — mechanism propensity

0.5869th %ile

GOF

0.6443th %ile

LOF

0.52top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.30

GOFprediction above median · 91% of P/LP are missense

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

139 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic6

VUS62

Likely Benign15

Benign3

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	1	0	5
Likely Pathogenic	0	6	0	0	6
VUS	3	51	7	1	62
Likely Benign	0	6	3	6	15
Benign	0	0	2	1	3
Conflicting	—				1
Total	3	67	13	8	92

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

View in ClinVar →

69 pathogenic / likely-pathogenic (of 73) ClinVar copy-number / structural variants overlap GLRA2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →