GLRA1

Chr 5ADAR

glycine receptor alpha 1

Also known as: HKPX1, STHE

NCBI Gene: 2741ENSG00000145888UniProt: P23415

The protein encoded by this gene is a subunit of a pentameric inhibitory glycine receptor, which mediates postsynaptic inhibition in the central nervous system. Defects in this gene are a cause of startle disease (STHE), also known as hereditary hyperekplexia or congenital stiff-person syndrome. Multiple transcript variants encoding different isoforms have been found. [provided by RefSeq, Dec 2015]

Primary Disease Associations & Inheritance

Hyperekplexia 1MIM #149400
ADAR
397
ClinVar variants
74
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— GLRA1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
74 Pathogenic / Likely Pathogenic· 142 VUS of 397 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.76LOEUF
pLI 0.000
Z-score 2.41
OE 0.45 (0.28–0.76)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.42Z-score
OE missense 0.75 (0.67–0.85)
195 obs / 259.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.45 (0.28–0.76)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.67–0.85)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.00
0≤1.21.6
LoF obs/exp: 10 / 22.3Missense obs/exp: 195 / 259.4Syn Z: 0.02

ClinVar Variant Classifications

397 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic52
Likely Pathogenic22
VUS142
Likely Benign137
Benign30
Conflicting14
52
Pathogenic
22
Likely Pathogenic
142
VUS
137
Likely Benign
30
Benign
14
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
15
27
0
52
Likely Pathogenic
7
14
1
0
22
VUS
0
120
21
1
142
Likely Benign
0
6
60
71
137
Benign
0
2
25
3
30
Conflicting
—14
Total1715713475397

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

View in ClinVar →

Protein Context — Lollipop Plot

GLRA1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

GLRA1-related hyperexplexia

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

GLRA1-related hyperexplexia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Hyperekplexia 1

MIM #149400

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
📖
GeneReview available — GLRA1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Myoclonus.
Espay AJ et al.·Continuum (Minneap Minn)
2013Review
Startle syndromes.
Bakker MJ et al.·Lancet Neurol
2006Review
Hereditary Hyperekplexia: A New Family and a Systematic Review of GLRA1 Gene-Related Phenotypes.
Ferraroli E et al.·Pediatr Neurol
2022Review
Hyperekplexia: A Single-Center Experience.
Dolu MH et al.·J Child Neurol
2024
Hereditary Hyperekplexia in Saudi Arabia.
Aldhilan A et al.·Pediatr Neurol
2022
Startle syndromes.
Bhidayasiri R et al.·Handb Clin Neurol
2011
A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia.
Heinonen T et al.·Hum Genet
2023
Hyperekplexia: a treatable neurogenetic disease.
Zhou L et al.·Brain Dev
2002Review
Neonatal Hyperekplexia: Is It Still a Diagnostic Challenge? Evidence From a Systematic Review.
Falsaperla R et al.·J Child Neurol
2024Review
STARDEV Study: Neurodevelopmental Trajectory and Long-Term Outcomes of Patients with Startle Disease/Hyperekplexia.
Pina D et al.·Mov Disord Clin Pract
2025Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Hyperekplexia

Hyperekplexia : Adaptative Skills and Neurodevelopmental Trajectory

RECRUITING
NCT05652101Hospices Civils de LyonStarted 2023-04-24
collection of medical dataVineland Adaptive Behaviour Scales (VABS2) questionnaire
Refractory Lupus NephritisMyasthaenia GravisStiff Person Syndrome

A Long-Term Follow-Up Study for Participants Previously Treated With KYV-101

RECRUITING
NCT07403188Kyverna TherapeuticsStarted 2025-11-24
KYV-101

External Resources

Links to major genomics databases and tools