# NM_000321.3(RB1):c.1186C>T (p.Pro396Ser)

https://sugi.bio/variant/rb1-p-pro396ser

## Summary

**RB1 p.Pro396Ser (c.1186C>T)** is classified **Uncertain significance** in RB1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-06). AlphaMissense: likely pathogenic (0.9326); Absent from gnomAD v4.1; Associated with retinoblastoma.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2138131224 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the RB1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to retinoblastoma.

*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, Not applicable |
| Age of onset (of this condition) | Antenatal, Childhood, Infancy |
| Prevalence | <1 / 1 000 000 (Europe) |
| Clinical trials | 106 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | RB1 is a diagnostic-grade gene on 7 Genomics England panels |

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

- Retinoblastoma — Obligate (100%)
- Strabismus — Frequent (79-30%)
- Glaucoma — Frequent (79-30%)
- Proptosis — Frequent (79-30%)
- Leukocoria — Frequent (79-30%)
- Hypopyon — Frequent (79-30%)
- Uveitis — Occasional (29-5%)
- Heterochromia iridis — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007563/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RB1](https://sugi.bio/atlas/gene/RB1/) |
| Protein change (HGVS p.) | p.Pro396Ser |
| Coding change (HGVS c.) | c.1186C>T |
| MANE Select transcript | [NM_000321](https://www.ncbi.nlm.nih.gov/nuccore/NM_000321) |
| dbSNP | [rs2138131224](https://www.ncbi.nlm.nih.gov/snp/rs2138131224/) |
| Variant type | single nucleotide variant |
| Location | chr13:48373463-48373463 (GRCh38) |
| ClinVar | [VCV2845302](https://www.ncbi.nlm.nih.gov/clinvar/variation/2845302/) |

**All HGVS expressions:** `LRG_517:g.74717C>T`, `LRG_517t1:c.1186C>T`, `NC_000013.10:g.48947599C>T`, `NC_000013.11:g.48373463C>T`, `NG_009009.1:g.74717C>T`, `NM_000321.3:c.1186C>T`, `NM_001407165.1:c.1186C>T`, `NM_001407166.1:c.1186C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9326)
- REVEL 0.876 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.081 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.601, GERP 1.66, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.1**. 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.*
- Regional missense constraint: **o/e 0.81** across the covering region of the MANE Select transcript (48,303,913–48,459,724), spanning 155,811 bp. Chi-square p 9.1e-08. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**RB1** population constraint: LOEUF 0.239, pLI 1, missense-Z 2.32; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **retinoblastoma** — Definitive (AD)

## Protein context {#protein}

Residue **396** lies in the 'pocket; binds t and e1a' region; the 'domain a' region.

AlphaFold model confidence (whole protein): pLDDT 77.03, 53% of residues very-high.

**19 experimental structure(s)** (PDB): [1AD6](https://www.rcsb.org/structure/1AD6), [1GH6](https://www.rcsb.org/structure/1GH6), [1GUX](https://www.rcsb.org/structure/1GUX), [1H25](https://www.rcsb.org/structure/1H25), [1N4M](https://www.rcsb.org/structure/1N4M), [1O9K](https://www.rcsb.org/structure/1O9K).

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

*Describes the biological roles of RB1 (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:** RB1's established molecular role includes kinase binding. p.Pro396Ser falls in the pocket; binds t and e1a region. In Reactome, RB1 is annotated in disease pathway(s) including **Aberrant regulation of mitotic exit in cancer due to RB1 defects**, **Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)**.

**Disease mechanism (Reactome):** RB1 loss or alteration is curated in [Aberrant regulation of mitotic exit in cancer due to RB1 defects](https://reactome.org/content/detail/R-HSA-9687136), [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069), [Defective translocation of RB1 mutants to the nucleus](https://reactome.org/content/detail/R-HSA-9661070).

### Pathways affected {#pathways}

RB1 participates in **18 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Aberrant regulation of mitotic exit in cancer due to RB1 defects](https://reactome.org/content/detail/R-HSA-9687136) | curated |
| ⚕ [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069) | curated |
| ⚕ [Defective translocation of RB1 mutants to the nucleus](https://reactome.org/content/detail/R-HSA-9661070) | curated |
| ⚕ [Nuclear events stimulated by ALK signaling in cancer](https://reactome.org/content/detail/R-HSA-9725371) | curated |
| ⚕ [Replication of the SARS-CoV-1 genome](https://reactome.org/content/detail/R-HSA-9682706) | curated |
| ⚕ [Replication of the SARS-CoV-2 genome](https://reactome.org/content/detail/R-HSA-9694686) | electronic |
| [APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1](https://reactome.org/content/detail/R-HSA-174178) | curated |
| [Condensation of Prophase Chromosomes](https://reactome.org/content/detail/R-HSA-2299718) | 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 |
| [Formation of Senescence-Associated Heterochromatin Foci (SAHF)](https://reactome.org/content/detail/R-HSA-2559584) | curated |
| [MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis](https://reactome.org/content/detail/R-HSA-9841922) | curated |
| [Oncogene Induced Senescence](https://reactome.org/content/detail/R-HSA-2559585) | curated |
| [Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes](https://reactome.org/content/detail/R-HSA-69200) | curated |
| [Positive Regulation of CDH1 Gene Transcription](https://reactome.org/content/detail/R-HSA-9764790) | curated |
| [Inhibition of replication initiation of damaged DNA by RB1/E2F1](https://reactome.org/content/detail/R-HSA-113501) | electronic |
| [RUNX2 regulates osteoblast differentiation](https://reactome.org/content/detail/R-HSA-8940973) | electronic |

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

**Molecular function:** kinase binding, ubiquitin protein ligase binding, identical protein binding, phosphoprotein binding, molecular adaptor activity, importin-alpha family protein binding.

**Biological process:** regulation of DNA-templated transcription, negative regulation of protein kinase activity, Ras protein signal transduction, regulation of mitotic cell cycle, negative regulation of gene expression, sister chromatid biorientation.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-02-06.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-08 |

## Associated conditions {#conditions}

[retinoblastoma](https://sugi.bio/atlas/disease/retinoblastoma/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Retinoblastoma, Hereditary cancer-predisposing syndrome, RETINOBLASTOMA, SOMATIC, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Tumor predisposition.

## Similar variants {#similar}

Related RB1 variant pages (same residue, condition, or type): [RB1 c.1049+1G>A](/variant/rb1-c-1049-plus-1g-a), [RB1 c.1049+1G>T](/variant/rb1-c-1049-plus-1g-t), [RB1 c.1049+3A>G](/variant/rb1-c-1049-plus-3a-g), [RB1 c.1050-2A>G](/variant/rb1-c-1050-minus-2a-g), [RB1 c.1128-1G>A](/variant/rb1-c-1128-minus-1g-a), [RB1 c.1128-2A>G](/variant/rb1-c-1128-minus-2a-g), [RB1 c.1215+1G>A](/variant/rb1-c-1215-plus-1g-a), [RB1 c.1215+1G>C](/variant/rb1-c-1215-plus-1g-c).

### 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 2845302). 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.*