# NM_001283009.2(RTEL1):c.2410T>C (p.Ser804Pro)

https://sugi.bio/variant/rtel1-p-ser804pro

## Summary

**RTEL1 p.Ser804Pro (c.2410T>C)** is classified **Uncertain significance** in RTEL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-05). AlphaMissense: likely benign (0.0686); Very rare (popmax 6.53e-05%); Associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2145432315 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 6.53e-05%)

## For patients & families {#patients}

This is a change in the RTEL1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016098/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RTEL1](https://sugi.bio/atlas/gene/RTEL1/) |
| Protein change (HGVS p.) | p.Ser804Pro |
| Coding change (HGVS c.) | c.2410T>C |
| MANE Select transcript | [NM_001283009](https://www.ncbi.nlm.nih.gov/nuccore/NM_001283009) |
| dbSNP | [rs2145432315](https://www.ncbi.nlm.nih.gov/snp/rs2145432315/) |
| Variant type | single nucleotide variant |
| Location | chr20:63690438-63690438 (GRCh38) |
| ClinVar | [VCV1422268](https://www.ncbi.nlm.nih.gov/clinvar/variation/1422268/) |

**All HGVS expressions:** `LRG_1149:g.37629T>C`, `LRG_1149t1:c.2482T>C`, `LRG_1149t2:c.2410T>C`, `LRG_1149t3:c.2410T>C`, `NC_000020.10:g.62321791T>C`, `NC_000020.11:g.63690438T>C`, `NG_033901.1:g.37629T>C`, `NM_001283009.2:c.2410T>C`, `NM_001283010.1:c.1741T>C`, `NM_016434.4:c.2410T>C`, `NM_032957.5:c.2482T>C`, `NR_037882.1:n.3237T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0686)
- REVEL 0.016 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.591 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -4.18, GERP -2.45 — fast-evolving / accelerated position
- CADD: **PHRED 3.476**. 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 1.45** across the covering region of the MANE Select transcript (63,690,297–63,695,855), spanning 5,558 bp. Chi-square p 3.7e-34. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.54 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): global (via dbSNP) **6.53e-05%** · 1/1,532,564 alleles overall — very rare (popmax 6.53e-05%).

*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}

**RTEL1** population constraint: LOEUF 0.661, pLI 1.271e-13, missense-Z -1.5797. *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):

- **pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3** — Definitive (SD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 72.64, 40% of residues very-high.

**3 experimental structure(s)** (PDB): [7WU8](https://www.rcsb.org/structure/7WU8), [8P8H](https://www.rcsb.org/structure/8P8H), [8YA8](https://www.rcsb.org/structure/8YA8).

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

*Describes the biological roles of RTEL1 (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:** RTEL1's established molecular role includes DNA helicase activity.


### Pathways affected {#pathways}

RTEL1 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)](https://reactome.org/content/detail/R-HSA-5693554) | curated |
| [Telomere Extension By Telomerase](https://reactome.org/content/detail/R-HSA-171319) | curated |
| [Cytosolic iron-sulfur cluster assembly](https://reactome.org/content/detail/R-HSA-2564830) | electronic |

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

**Molecular function:** DNA helicase activity, ATP binding.

**Biological process:** telomere maintenance, regulation of double-strand break repair via homologous recombination, telomeric loop disassembly, positive regulation of telomere capping, positive regulation of telomere maintenance via telomere lengthening, negative regulation of t-circle formation.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-05.

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

**Submission history:** 2 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-24 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-05 |

## Associated conditions {#conditions}

[pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3](https://sugi.bio/atlas/disease/pulmonary-fibrosis-and-or-bone-marrow-failure-telomere-related-3/), [dyskeratosis congenita, autosomal recessive 5](https://sugi.bio/atlas/disease/dyskeratosis-congenita-autosomal-recessive-5/).

**Reported phenotype names (ClinVar):** Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3, Dyskeratosis congenita, autosomal recessive 5, Inborn genetic diseases, PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 3.

## Similar variants {#similar}

Related RTEL1 variant pages (same residue, condition, or type): [RTEL1 p.Ser804Leu](/variant/rtel1-p-ser804leu), [RTEL1 c.1037+1G>T](/variant/rtel1-c-1037-plus-1g-t), [RTEL1 c.1192-2A>G](/variant/rtel1-c-1192-minus-2a-g), [RTEL1 c.1596-1G>A](/variant/rtel1-c-1596-minus-1g-a), [RTEL1 c.2142-1G>C](/variant/rtel1-c-2142-minus-1g-c), [RTEL1 c.2265+1G>T](/variant/rtel1-c-2265-plus-1g-t), [RTEL1 c.2413+1G>A](/variant/rtel1-c-2413-plus-1g-a), [RTEL1 c.2413+1G>C](/variant/rtel1-c-2413-plus-1g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1422268). 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.*