SAG
protein-codingS-antigen visual arrestin, the group of Classical arrestins
Gene summary
Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G-protein-coupled receptors and cause specific dampening of cellular responses to stimuli such as hormones, neurotransmitters, or sensory signals. S-arrestin, also known as S-antigen, is a major soluble photoreceptor protein that is involved in desensitization of the photoactivated transduction cascade. It is expressed in the retina and the pineal gland and inhibits coupling of rhodopsin to transducin in vitro. Additionally, S-arrestin is highly antigenic, and is capable of inducing experimental autoimmune uveoretinitis. Mutations in this gene have been associated with Oguchi disease, a rare autosomal recessive form of night blindness. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~39.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0019152
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0859367
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013407
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009775
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009775
Submitter: G2P
Inheritance Pattern: SD
Disease ID:MONDO:0013407
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009775
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0005283
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013407
Submitter: ClinGen
The *SAG* gene, which encodes the photoreceptor protein arrestin-1, was first reported in relation to autosomal recessive retinal disease in 1995 (Fuchs et al. 1995; PMID 7670478). SAG-related recessive retinopathy, including Oguchi disease and retinitis pigmentosa, is a rare retinal disease; Oguchi disease characterized by classic presentation of night blindness and a distinctive fundus appearance termed the Mizuo-Nakamura Phenomenon, thought to be pathognomonic for the disease (PMID: 31014762), whereas retinitis pigmentosa is characterized by constriction of visual fields. There have been reports of Oguchi disease progressing to retinitis pigmentosa (PMID: 31864474). We found *SAG*-related disease is primarily inherited in an autosomal recessive pattern, with biallelic disease-causing *SAG* variants resulting in a spectrum of phenotypes including Oguchi disease and retinitis pigmentosa. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found the molecular mechanism (biallelic loss of function in the *SAG* gene product) and mode of inheritance (autosomal recessive) to be consistent among unrelated patients diagnosed with either Oguchi disease or retinitis pigmentosa, while the phenotypic variability between them appeared to represent a spectrum of disease rather than separate disease entities. Because the cases different diagnoses all exhibit a recessive mode of inheritance and share overlapping phenotypes consistent with a single spectrum of disease, and consistent with criteria outlined by the ClinGen Lumping and Splitting Working Group, these cases have been lumped into a single disease entity, *SAG*-related recessive retinopathy. An additional disease entity has been asserted in relation to a monoallelic variant in *SAG*, specifically a substitution at codon 147 that encodes phenylalanine rather than cysteine (PMID: 28549094, 29305604). While this disease entity is characterized by similar retinal dystrophy, its different mode of inheritance and unique variant suggested a different mechanism of pathogenesis. Thus, *SAG* was separately curated for its relationship to this disease entity, referred to as *SAG*-related dominant retinopathy. This curation includes eight suspected disease-causing variants (four nonsense, one frameshift, and three canonical splicing variants) that have been reported in seven probands in five publications (PMID: 9452120, PMID: 15234147, PMID: 22665972, PMID: 35549688, PMID: 38219857). Homozygous variants in families from multiple countries were included in the curation (PMID: 20537394, PMID: 21069908, PMID: 18836446) from both consanguineous and non-consanguineous families. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity appears to be loss of function, as multiple nonsense or frameshift mutations resulting in SAG-related disease are described in the literature (PMID: 20537394, PMID: 21069908, PMID: 18836446). To date, most reported variants are nonsense, frameshift and splicing variants. This gene-disease association is supported by multiple model systems, including murine and canine models, that demonstrates phenotypes consistent with retinal degeneration (PMID: 18985007, PMID: 24019744). Expression of *SAG* has also been validated in human retinal tissue (PMID: 229466423). Biochemical studies have demonstrated that the SAG-encoded arrestin-1 impacts the activity of the retinal protein rhodopsin (PMID: 24921014, PMID: 39704710). In summary, *SAG* is Definitively associated with *SAG*-related recessive retinopathy. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of conflicting evidence. This classification has been approved by the ClinGen Retina GCEP on January 15th, 2026 (SOP Version 11).
Clinical Genomic Database (CGD)
Manifestation: Ophthalmologic
Intervention: General
Rationale: Manifesting heterozygotes have been described; Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SAG variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000541.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 9 | 75 | 2 | 87 | |
| missense | 1 | 3 | 223 | 11 | 238 | |
| nonsense | 6 | 2 | 1 | 9 | ||
| start loss | 0 | |||||
| frameshift | 6 | 4 | 3 | 13 | ||
| splice donor/acceptor (+/-2bp) | 2 | 23 | 1 | 26 | ||
| Total | 15 | 33 | 237 | 86 | 2 | 373 |
Highest pathogenic variant AF is 0.00016915085
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000532.2 | 15 | MANE Select | |
| Ensembl | ENSP00000386444.1 | 15 | MANE Select | |
| Ensembl | ENSP00000409475.1 | 3 | Standard | |
| Ensembl | ENSP00000408937.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Phototransduction - Homo sapiens (human)
- Signaling by GPCR
- Signal Transduction
- Visual signal transduction: Rods
- G alpha (i) signalling events
Biological Process
- cell surface receptor signaling pathway
- rhodopsin mediated signaling pathway
- regulation of rhodopsin mediated signaling pathway
- negative regulation of phosphoprotein phosphatase activity
Molecular Function
- opsin binding
- protein phosphatase inhibitor activity
- phosphoprotein binding
Cellular Component
- photoreceptor outer segment
- photoreceptor inner segment
- cytosol
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000409110
- Coding exons
- 15
- Length
- 39240
- Individuals with no LoFs
- 124882
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 112
- Defined
- 124994
- p
- 0.000448
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.685 | 201 | 230 | 0.873 | 0.0000135 | 2613 |
| Missense (PolyPhen) | 73 | 86.476 | 0.84417 | 1029 | ||
| Synonymous | 1.04 | 81 | 93.9 | 0.863 | 0.00000602 | 767 |
| Loss of Function | -0.101 | 24 | 23.5 | 1.02 | 0.00000123 | 281 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0015 | 0.0013 | notable |
| Latino/Admixed American | 0.00043 | 0.00041 | rare |
| Ashkenazi Jewish | 0.00040 | 0.00040 | rare |
| East Asian | 0.00056 | 0.00055 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00027 | 0.00026 | rare |
| South Asian | 0.0010 | 0.0010 | notable |
| Other | 0.00050 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Binds to photoactivated, phosphorylated RHO and terminates RHO signaling via G-proteins by competing with G- proteins for the same binding site on RHO (By similarity). May play a role in preventing light-dependent degeneration of retinal photoreceptor cells (PubMed:9565049). {ECO:0000250|UniProtKB:P08168, ECO:0000305|PubMed:9565049}.;
- Disease
- DISEASE: Night blindness, congenital stationary, Oguchi type 1 (CSNBO1) [MIM:258100]: A non-progressive retinal disorder characterized by impaired night vision, often associated with nystagmus and myopia. Congenital stationary night blindness Oguchi type is an autosomal recessive form associated with fundus discoloration and abnormally slow dark adaptation. {ECO:0000269|PubMed:7670478}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Retinitis pigmentosa 47 (RP47) [MIM:613758]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:9565049}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.463
Intolerance Scores
- LoFtool
- 0.882
- RVIS EVS
- 0.29
- RVIS percentile EVS
- 71.57
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.591
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |