Is RS1 p.Arg174fs (c.520del) pathogenic?

RS1 p.Arg174fs (c.520del) is classified Pathogenic in RS1 (ClinVar, Expert panel, 4 submitters; last evaluated 2025-05-19). No gnomAD frequency available for this variant; Associated with X-linked retinoschisis.

What condition is associated with RS1 p.Arg174fs (c.520del)?

RS1 p.Arg174fs (c.520del) is associated with X-linked retinoschisis (ClinVar).

How common is RS1 p.Arg174fs (c.520del) in the general population?

RS1 p.Arg174fs (c.520del) is no gnomAD frequency available for this variant (gnomAD).

RS1 p.Arg174fs

c.520del · rs886041235 · VCV279886

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

X-linked retinoschisis

ClinGen expert panel — X-linked Inherited Retinal Disease VCEP

Pathogenic for X-linked retinoschisis. Applied ACMG criteria (verbatim):

PVS1 PM2_Supporting PS4_Supporting

Curation rationale (ClinGen, verbatim)

The NM_000330.4(RS1):c.520del variant is a frameshift variant due to 1 nucleotide deletion introducing a premature stop codon and causing a truncated protein. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This is a frameshift variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID: 19849666). This variant has been reported in at least 2 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMIDs: 30551202, 17852193, PS4_Supporting). In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PM2_supporting, PVS1, and PS4_supporting (date of approval 01/24/2025).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: RS1
Protein: p.Arg174fs
Coding: c.520del
MANE Select: NM_001323289 · reported on NM_000330
dbSNP: rs886041235
Type: Deletion
Location: chrX:18644432 (GRCh38)

Full RS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

X-linked retinoschisis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rs1-p-arg174fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown