# NM_001283009.2(RTEL1):c.2353T>C (p.Ser785Pro)

https://sugi.bio/variant/rtel1-p-ser785pro

## Summary

**RTEL1 p.Ser785Pro (c.2353T>C)** is classified **Uncertain significance** in RTEL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-26). AlphaMissense: likely benign (0.0561); Very rare (popmax 8.49e-05%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 8.49e-05%, nfe)

## 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 1 submitter, and is linked to Inborn genetic diseases.

*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:** [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.Ser785Pro |
| Coding change (HGVS c.) | c.2353T>C |
| MANE Select transcript | [NM_001283009](https://www.ncbi.nlm.nih.gov/nuccore/NM_001283009) |
| Variant type | single nucleotide variant |
| Location | chr20:63690381-63690381 (GRCh38) |
| ClinVar | [VCV4629572](https://www.ncbi.nlm.nih.gov/clinvar/variation/4629572/) |

**All HGVS expressions:** `LRG_1149:g.37572T>C`, `LRG_1149t1:c.2425T>C`, `LRG_1149t2:c.2353T>C`, `LRG_1149t3:c.2353T>C`, `NC_000020.10:g.62321734T>C`, `NC_000020.11:g.63690381T>C`, `NG_033901.1:g.37572T>C`, `NM_001283009.2:c.2353T>C`, `NM_001283010.1:c.1684T>C`, `NM_016434.4:c.2353T>C`, `NM_032957.5:c.2425T>C`, `NR_037882.1:n.3180T>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** (0.0561)
- REVEL 0.002 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.46 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -1.437, GERP -2.42 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.333**. 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, Δ0.25 acceptor loss), 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): grpmax **8.49e-05%** (nfe) · 1/1,177,684 in the highest group · 1/1,608,552 alleles overall — very rare (popmax 8.49e-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}

**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}

Residue **785** lies in the 'disordered' region.

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. p.Ser785Pro falls in the disordered region.


### 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-26.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-26 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related RTEL1 variant pages (same residue, condition, or type): [RTEL1 p.Ser785=](/variant/rtel1-p-ser785), [RTEL1 p.Ala1012Ser](/variant/rtel1-p-ala1012ser), [RTEL1 p.Ala1052Thr](/variant/rtel1-p-ala1052thr), [RTEL1 p.Ala1074Val](/variant/rtel1-p-ala1074val), [RTEL1 p.Ala1085Val](/variant/rtel1-p-ala1085val), [RTEL1 p.Ala1101Thr](/variant/rtel1-p-ala1101thr), [RTEL1 p.Ala112Val](/variant/rtel1-p-ala112val), [RTEL1 p.Ala1240Pro](/variant/rtel1-p-ala1240pro).

### 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 4629572). 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.*