RS1

Chr X

retinoschisin 1

Also known as: RS, XLRS1

NCBI Gene: 6247 ENSG00000102104 UniProt: O15537

The RS1 protein is secreted by retinal photoreceptors and bipolar cells as oligomeric complexes that bind membrane lipids and mediate cell-cell adhesion to maintain normal retinal structure. Mutations cause X-linked retinoschisis, an early-onset macular degeneration in males characterized by splitting of the inner retinal layers and severe vision loss. This gene is highly constrained against loss-of-function variants (pLI 0.96, LOEUF 0.30) and follows X-linked recessive inheritance.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtRetinoschisis juvenile X-linked 1

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · X-linked retinoschisis · XL · ClinGen 2020

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

110

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.30

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — RS1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 0.957

Z-score 2.91

OE 0.00 (0.00–0.30)

Highly constrained

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

Missense Constraint?

0.97Z-score

OE missense 0.73 (0.61–0.89)

75 obs / 102.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.30)

0≤0.351.4

Missense OE?0.73 (0.61–0.89)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 0 / 9.9Missense obs/exp: 75 / 102.6Syn Z: 0.92

Background carrier burden — how many people carry a rare variant somewhere in RS1?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 270

164 rare PASS variants

Rare truncating (LoF)

1 in 39,000

8 rare PASS variants

Rare synonymous (reference)

1 in 430

76 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RS1. 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 280	1 in 27,000
South Asian	~36k	1 in 360	≈ 1 in 18,000
Remaining (unassigned)	~31k	1 in 210	≈ 1 in 15,000
European (Finnish)	~27k	1 in 1,400	none seen
Admixed American	~23k	1 in 380	none seen
African / African American	~21k	1 in 350	none seen
East Asian	~20k	1 in 540	none seen
Ashkenazi Jewish	~13k	≈ 1 in 6,500	none seen
Middle Eastern	~2,757	1 in 300	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): All 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓