# NM_002900.3(RBP3):c.1778T>C (p.Val593Ala)

https://sugi.bio/variant/rbp3-p-val593ala

## Summary

**RBP3 p.Val593Ala (c.1778T>C)** is classified **Uncertain significance** in RBP3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2013-06-27). AlphaMissense: ambiguous (0.4921); Very rare (popmax 0.000254%, nfe); Associated with retinitis pigmentosa 66.

**At a glance:** Uncertain significance · review: No assertion criteria · rsID rs782233167 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the RBP3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to retinitis pigmentosa 66.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |

**Commonly reported features of Retinitis pigmentosa** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Conductive hearing impairment — Very frequent (99-80%)
- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Retinal degeneration — Very frequent (99-80%)
- Photophobia — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015923/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RBP3](https://sugi.bio/atlas/gene/RBP3/) |
| Protein change (HGVS p.) | p.Val593Ala |
| Coding change (HGVS c.) | c.1778T>C |
| MANE Select transcript | [NM_002900](https://www.ncbi.nlm.nih.gov/nuccore/NM_002900) |
| dbSNP | [rs782233167](https://www.ncbi.nlm.nih.gov/snp/rs782233167/) |
| Variant type | single nucleotide variant |
| Location | chr10:47350262-47350262 (GRCh38) |
| ClinVar | [VCV208309](https://www.ncbi.nlm.nih.gov/clinvar/variation/208309/) |

**All HGVS expressions:** `NC_000010.10:g.48389100A>G`, `NC_000010.11:g.47350262T>C`, `NG_029718.1:g.6892T>C`, `NM_002900.3:c.1778T>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4921) — no call either way
- SaProt LLR -10.415 (damaging)
- Conservation: phyloP 3.034, GERP 1.44, phastCons 1 — highly conserved
- CADD: **PHRED 21.3**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,920 in the highest group · 3/1,607,468 alleles overall — very rare (popmax 0.000254%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**RBP3** population constraint: ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 63.40, 24% of residues very-high.

**8 experimental structure(s)** (PDB): [1H24](https://www.rcsb.org/structure/1H24), [1O9K](https://www.rcsb.org/structure/1O9K), [2AZE](https://www.rcsb.org/structure/2AZE), [5M9N](https://www.rcsb.org/structure/5M9N), [5M9O](https://www.rcsb.org/structure/5M9O), [6G0P](https://www.rcsb.org/structure/6G0P).

## What this gene does {#gene-function}

*Describes the biological roles of RBP3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** RBP3's established molecular role includes DNA-binding transcription factor activity, RNA polymerase II-specific. In Reactome, RBP3 is annotated in disease pathway(s) including **Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)**.

**Disease mechanism (Reactome):** RBP3 loss or alteration is curated in [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069).

### Pathways affected {#pathways}

RBP3 participates in **17 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069) | curated |
| [Activation of NOXA and translocation to mitochondria](https://reactome.org/content/detail/R-HSA-111448) | curated |
| [Activation of PUMA and translocation to mitochondria](https://reactome.org/content/detail/R-HSA-139915) | curated |
| [Cyclin A:Cdk2-associated events at S phase entry](https://reactome.org/content/detail/R-HSA-69656) | curated |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | curated |
| [Cyclin E associated events during G1/S transition ](https://reactome.org/content/detail/R-HSA-69202) | curated |
| [G2 Phase](https://reactome.org/content/detail/R-HSA-68911) | curated |
| [Oncogene Induced Senescence](https://reactome.org/content/detail/R-HSA-2559585) | curated |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |
| [TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest](https://reactome.org/content/detail/R-HSA-6804116) | curated |
| [Transcriptional Regulation by E2F6](https://reactome.org/content/detail/R-HSA-8953750) | curated |
| [G1/S-Specific Transcription](https://reactome.org/content/detail/R-HSA-69205) | electronic |
| [Inhibition of replication initiation of damaged DNA by RB1/E2F1](https://reactome.org/content/detail/R-HSA-113501) | electronic |
| [Pre-NOTCH Transcription and Translation](https://reactome.org/content/detail/R-HSA-1912408) | electronic |
| [Transcription of E2F targets under negative control by DREAM complex](https://reactome.org/content/detail/R-HSA-1362277) | electronic |
| [Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1](https://reactome.org/content/detail/R-HSA-1362300) | electronic |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** DNA-binding transcription factor activity, RNA polymerase II-specific, cis-regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA binding, DNA-binding transcription factor activity.

**Biological process:** DNA damage checkpoint signaling, negative regulation of transcription by RNA polymerase II, regulation of DNA-templated transcription, intrinsic apoptotic signaling pathway in response to DNA damage, positive regulation of gene expression, positive regulation of apoptotic process.

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2013-06-27.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ClinVar Staff, National Center for Biotechnology Information (NCBI) | Uncertain significance | no assertion criteria provided | literature only | 2013-06-27 |

## Associated conditions {#conditions}

[retinitis pigmentosa 66](https://sugi.bio/atlas/disease/retinitis-pigmentosa-66/).

**Reported phenotype names (ClinVar):** Retinitis pigmentosa 66.

## Similar variants {#similar}

Related RBP3 variant pages (same residue, condition, or type): [RBP3 p.Val593Met](/variant/rbp3-p-val593met), [RBP3 p.Val593Leu](/variant/rbp3-p-val593leu), [RBP3 p.Arg388Ter](/variant/rbp3-p-arg388ter), [RBP3 p.Gln54Ter](/variant/rbp3-p-gln54ter), [RBP3 p.Ala325Thr](/variant/rbp3-p-ala325thr), [RBP3 p.Ala379Thr](/variant/rbp3-p-ala379thr), [RBP3 p.Ala688Val](/variant/rbp3-p-ala688val), [RBP3 p.Arg170Gln](/variant/rbp3-p-arg170gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 208309). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*