RS1

Chr XXLR

retinoschisin 1

Also known as: RS, XLRS1

NCBI Gene: 6247ENSG00000102104UniProt: O15537

This gene encodes an extracellular protein that plays a crucial role in the cellular organization of the retina. The encoded protein is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Mutations in this gene are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. [provided by RefSeq, Oct 2008]

Primary Disease Associations & Inheritance

RetinoschisisMIM #312700
XLR
RetinoschisisMIM #312700
XLR
UniProtRetinoschisis juvenile X-linked 1
472
ClinVar variants
179
Pathogenic / LP
0.96
pLI score· haploinsufficient
5
Active trials
Clinical Summary— RS1
🧬
Gene-Disease Validity (ClinGen)
X-linked retinoschisis · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
179 Pathogenic / Likely Pathogenic· 136 VUS of 472 total submissions
💊
Clinical Trials
5 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.30LOEUF
pLI 0.957
Z-score 2.91
OE 0.00 (0.00–0.30)
Highly constrained

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

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.
0.97Z-score
OE missense 0.73 (0.61–0.89)
75 obs / 102.6 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.0.00 (0.00–0.30)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.61–0.89)
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.0.82
0≤1.21.6
LoF obs/exp: 0 / 9.9Missense obs/exp: 75 / 102.6Syn Z: 0.92

ClinVar Variant Classifications

472 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic106
Likely Pathogenic73
VUS136
Likely Benign138
Benign10
Conflicting9
106
Pathogenic
73
Likely Pathogenic
136
VUS
138
Likely Benign
10
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
28
18
60
0
106
Likely Pathogenic
10
55
8
0
73
VUS
4
94
38
0
136
Likely Benign
1
11
54
72
138
Benign
0
1
8
1
10
Conflicting
—9
Total4317916873472

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

View in ClinVar →

Protein Context — Lollipop Plot

RS1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

RS1-related retinoschisis

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM
RETINOSCHISIN; RS1
MIM #300839 · *

Retinoschisis

MIM #312700

Molecular basis of disorder known

X-linked recessive

Retinoschisis

MIM #312700

Molecular basis of disorder known

X-linked recessive
📖
GeneReview available — RS1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
De Novo Mutations Contributes Approximately 7% of Pathogenicity in Inherited Eye Diseases.
Li W et al.·Invest Ophthalmol Vis Sci
2023
Macular dystrophies: clinical and imaging features, molecular genetics and therapeutic options.
Rahman N et al.·Br J Ophthalmol
2020Review
Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes.
Georgiou M et al.·Prog Retin Eye Res
2024Review
The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies.
De Silva SR et al.·Prog Retin Eye Res
2021Review
Diverse Genetic Landscape of Suspected Retinitis Pigmentosa in a Large Korean Cohort.
Kim YJ et al.·Genes (Basel)
2021Cohort
Panel-based genetic testing for inherited retinal disease screening 176 genes.
Sheck LHN et al.·Mol Genet Genomic Med
2021
X-Linked Retinoschisis.
Ku CA et al.·Cold Spring Harb Perspect Med
2023Review
Sodium-glucose cotransport.
Poulsen SB et al.·Curr Opin Nephrol Hypertens
2015Review
A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic Testing.
Areblom M et al.·Genes (Basel)
2023Cohort
Hereditary Retinal Dystrophy.
Hohman TC·Handb Exp Pharmacol
2017Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Case Report: Carbonic anhydrase inhibitor brinzolamide dramatically improved the morphology and also function of a patient with RS1 mutation.
Ren Y et al.·Front Pharmacol
2025🔓 Open AccessCase report
Retinal detachment associated with the splice site mutation c.53-1G>A in the RS1 gene: A case report and review of the literature.
Meng J et al.·SAGE Open Med Case Rep
2025🔓 Open AccessReview
Dark Rearing Does Not Alter Developmental Retinoschisis Cavity Formation in Rs1 Gene Knockout Rat Model of X-Linked Retinoschisis.
Smit-McBride Z et al.·Genes (Basel)
2025🔓 Open AccessFunctional
A novel deletion-insertion variant of RS1 in X-linked retinoschisis.
Higa N et al.·Ophthalmic Genet
2025
Intravitreal adenine base editing of RS1 improves vision in a preclinical mouse model of retinoschisis.
Jo DH et al.·Mol Ther
2025Functional
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
X-linked Retinoschisis

ATSN-201 Gene Therapy in RS1-Associated X-linked Retinoschisis

RECRUITING
NCT05878860Phase PHASE1, PHASE2Atsena Therapeutics Inc.Started 2023-08-22
ATSN-201
Age-Related Macular Degeneration

A Follow-up Study to Evaluate the Safety of RetinoStat® in Patients With Age-Related Macular Degeneration

ACTIVE NOT RECRUITING
NCT01678872Phase PHASE1Oxford BioMedicaStarted 2012-08
RetinoStat
RetinoschisisRetinal DiseaseRetinal Degeneration

Safety and Efficacy Study of IVB102 Injection in Subjects With X-linked Retinoschisis

ACTIVE NOT RECRUITING
NCT06289452Phase EARLY_PHASE1InnoVec Biotherapeutics Inc.Started 2024-03-08
IVB102 InjectionIVB102 InjectionIVB102 Injection
X-linked Retinoschisis

Safety and Efficacy Study of Novel Gene Therapy ZM-01 for X-linked Retinoschisis Patients

RECRUITING
NCT06066008Phase EARLY_PHASE1Zhongmou TherapeuticsStarted 2022-09-25
ZM-01-LZM-01-H
Retinoschisis

Clinical and Genetic Studies of X-Linked Juvenile Retinoschisis

ACTIVE NOT RECRUITING
NCT00055029National Eye Institute (NEI)Started 2003-05-19

External Resources

Links to major genomics databases and tools