# NM_001029.5(RPS26):c.307C>T (p.Pro103Ser)

https://sugi.bio/variant/rps26-p-pro103ser

## Summary

**RPS26 p.Pro103Ser (c.307C>T)** is classified **Uncertain significance** in RPS26 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-17). AlphaMissense: likely benign (0.3097); Very rare (popmax 8.48e-05%, nfe); Associated with Diamond-Blackfan anemia 10.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the RPS26 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Diamond-Blackfan anemia 10.

*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 |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Diagnostic panels | RPS26 is a diagnostic-grade gene on 11 Genomics England panels |

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

- Pure red cell aplasia — Very frequent (99-80%)
- Elevated red cell adenosine deaminase activity — Very frequent (99-80%)
- Abnormality of the head — Frequent (79-30%)
- Pallor — Frequent (79-30%)
- Lethargy — Frequent (79-30%)
- Growth delay — Frequent (79-30%)
- Small for gestational age — Frequent (79-30%)
- Reticulocytopenia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015645/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RPS26](https://sugi.bio/atlas/gene/RPS26/) |
| Protein change (HGVS p.) | p.Pro103Ser |
| Coding change (HGVS c.) | c.307C>T |
| MANE Select transcript | [NM_001029](https://www.ncbi.nlm.nih.gov/nuccore/NM_001029) |
| Variant type | single nucleotide variant |
| Location | chr12:56043488-56043488 (GRCh38) |
| ClinVar | [VCV3574995](https://www.ncbi.nlm.nih.gov/clinvar/variation/3574995/) |

**All HGVS expressions:** `LRG_1146:g.6587C>T`, `LRG_1146t1:c.307C>T`, `NC_000012.11:g.56437272C>T`, `NC_000012.12:g.56043488C>T`, `NG_023201.1:g.6587C>T`, `NM_001029.5:c.307C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.3097)
- REVEL 0.702 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -11.845 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 7.554, GERP 2.01, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.2**. 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 0.40** across the covering region of the MANE Select transcript (56,042,167–56,044,151), spanning 1,984 bp. Chi-square p 4.7e-14. 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 (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,906 in the highest group · 1/1,613,774 alleles overall — very rare (popmax 8.48e-05%, 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}

**RPS26** population constraint: LOEUF 0.32, pLI 0.99588, missense-Z 2.7399; 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.*

## Protein context {#protein}

Residue **103** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 86.09, 55% of residues very-high.

**185 experimental structure(s)** (PDB): [22TU](https://www.rcsb.org/structure/22TU), [28LN](https://www.rcsb.org/structure/28LN), [28ZU](https://www.rcsb.org/structure/28ZU), [28ZV](https://www.rcsb.org/structure/28ZV), [28ZX](https://www.rcsb.org/structure/28ZX), [28ZY](https://www.rcsb.org/structure/28ZY) — incl. mutant structure 28ZU.

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

*Describes the biological roles of RPS26 (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:** RPS26's established molecular role includes RNA binding. p.Pro103Ser falls in the disordered region. In Reactome, RPS26 is annotated in disease pathway(s) including **SARS-CoV-1 modulates host translation machinery**, **SARS-CoV-2 modulates host translation machinery**.

**Disease mechanism (Reactome):** RPS26 loss or alteration is curated in [SARS-CoV-1 modulates host translation machinery](https://reactome.org/content/detail/R-HSA-9735869), [SARS-CoV-2 modulates host translation machinery](https://reactome.org/content/detail/R-HSA-9754678), [Viral mRNA Translation](https://reactome.org/content/detail/R-HSA-192823).

### Pathways affected {#pathways}

RPS26 participates in **21 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-1 modulates host translation machinery](https://reactome.org/content/detail/R-HSA-9735869) | curated |
| ⚕ [SARS-CoV-2 modulates host translation machinery](https://reactome.org/content/detail/R-HSA-9754678) | curated |
| ⚕ [Viral mRNA Translation](https://reactome.org/content/detail/R-HSA-192823) | curated |
| [Formation of a pool of free 40S subunits](https://reactome.org/content/detail/R-HSA-72689) | curated |
| [Formation of the ternary complex, and subsequently, the 43S complex](https://reactome.org/content/detail/R-HSA-72695) | curated |
| [GTP hydrolysis and joining of the 60S ribosomal subunit](https://reactome.org/content/detail/R-HSA-72706) | curated |
| [IFIT antiviral response](https://reactome.org/content/detail/R-HSA-9684482) | curated |
| [L13a-mediated translational silencing of Ceruloplasmin expression](https://reactome.org/content/detail/R-HSA-156827) | curated |
| [Major pathway of rRNA processing in the nucleolus and cytosol](https://reactome.org/content/detail/R-HSA-6791226) | curated |
| [Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)](https://reactome.org/content/detail/R-HSA-975957) | curated |
| [Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)](https://reactome.org/content/detail/R-HSA-975956) | curated |
| [PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA](https://reactome.org/content/detail/R-HSA-9954714) | curated |
| [Ribosomal scanning and start codon recognition](https://reactome.org/content/detail/R-HSA-72702) | curated |
| [Translation initiation complex formation](https://reactome.org/content/detail/R-HSA-72649) | curated |
| [ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA](https://reactome.org/content/detail/R-HSA-9954716) | curated |
| [Eukaryotic Translation Termination](https://reactome.org/content/detail/R-HSA-72764) | electronic |
| [Peptide chain elongation](https://reactome.org/content/detail/R-HSA-156902) | electronic |
| [Regulation of expression of SLITs and ROBOs](https://reactome.org/content/detail/R-HSA-9010553) | electronic |
| [Response of EIF2AK4 (GCN2) to amino acid deficiency](https://reactome.org/content/detail/R-HSA-9633012) | electronic |
| [SRP-dependent cotranslational protein targeting to membrane](https://reactome.org/content/detail/R-HSA-1799339) | electronic |
| [Selenocysteine synthesis](https://reactome.org/content/detail/R-HSA-2408557) | electronic |

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

**Molecular function:** RNA binding, mRNA binding, structural constituent of ribosome, cadherin binding.

**Biological process:** cytoplasmic translation, negative regulation of RNA splicing.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-17.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-17 |

## Associated conditions {#conditions}

[Diamond-Blackfan anemia 10](https://sugi.bio/atlas/disease/diamond-blackfan-anemia-10/).

**Reported phenotype names (ClinVar):** Diamond-Blackfan anemia 10, RPS26-Related Diamond-Blackfan Anemia.

## Similar variants {#similar}

Related RPS26 variant pages (same residue, condition, or type): [RPS26 c.3+1G>T](/variant/rps26-c-3-plus-1g-t), [RPS26 c.3+2T>G](/variant/rps26-c-3-plus-2t-g), [RPS26 p.Arg28Ter](/variant/rps26-p-arg28ter), [RPS26 p.Arg87Ter](/variant/rps26-p-arg87ter), [RPS26 p.Gln19Ter](/variant/rps26-p-gln19ter), [RPS26 p.Met1Thr](/variant/rps26-p-met1thr), [RPS26 p.Met1Val](/variant/rps26-p-met1val), [RPS26 c.312+3G>A](/variant/rps26-c-312-plus-3g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3574995). 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.*