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…

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked syndromic, Pilorge typeMIM #301076

X-linked

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Intellectual developmental disorder, X-linked syndromic, Pilorge type; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.30

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

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

Background carrier burden — how many people carry a rare variant somewhere in GLRA2?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 430

241 rare PASS variants

Rare truncating (LoF)

1 in 13,000

21 rare PASS variants

Rare synonymous (reference)

1 in 390

149 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GLRA2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 460	1 in 26,000
South Asian	~36k	1 in 530	1 in 1,600
Remaining (unassigned)	~31k	1 in 460	1 in 5,000
European (Finnish)	~27k	1 in 3,000	≈ 1 in 27,000
Admixed American	~23k	1 in 290	none seen
African / African American	~21k	1 in 340	≈ 1 in 5,300
East Asian	~20k	1 in 360	≈ 1 in 20,000
Ashkenazi Jewish	~13k	≈ 1 in 6,400	≈ 1 in 4,300
Middle Eastern	~2,757	1 in 340	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 8 of 9 coding exons well covered in gnomAD exomes; exon 5 marginal. Genomes: all 9.? see exons ↓