# NM_001283009.2(RTEL1):c.703C>T (p.Arg235Cys)

https://sugi.bio/variant/rtel1-p-arg235cys

## Summary

**RTEL1 p.Arg235Cys (c.703C>T)** is classified **Uncertain significance** in RTEL1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-04). AlphaMissense: ambiguous (0.5032); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs866782181 · 3 submitters · 4 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.00134%, afr)

## 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 3 submitters, 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.Arg235Cys |
| Coding change (HGVS c.) | c.703C>T |
| MANE Select transcript | [NM_001283009](https://www.ncbi.nlm.nih.gov/nuccore/NM_001283009) |
| dbSNP | [rs866782181](https://www.ncbi.nlm.nih.gov/snp/rs866782181/) |
| Variant type | single nucleotide variant |
| Location | chr20:63672559-63672559 (GRCh38) |
| ClinVar | [VCV972517](https://www.ncbi.nlm.nih.gov/clinvar/variation/972517/) |

**All HGVS expressions:** `LRG_1149:g.19750C>T`, `LRG_1149t1:c.775C>T`, `LRG_1149t2:c.703C>T`, `LRG_1149t3:c.703C>T`, `NC_000020.10:g.62303912C>T`, `NC_000020.11:g.63672559C>T`, `NG_033901.1:g.19750C>T`, `NM_001283009.2:c.703C>T`, `NM_001283010.1:c.34C>T`, `NM_016434.4:c.703C>T`, `NM_032957.5:c.775C>T`, `NR_037882.1:n.1530C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.5032) — no call either way
- REVEL 0.693 (pathogenic-leaning)
- SaProt LLR -13.274 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- Conservation: phyloP 5.756, GERP 1.14, phastCons 1 — highly conserved
- CADD: **PHRED 27.7**. 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 0.86** across the covering region of the MANE Select transcript (63,659,403–63,690,296), spanning 30,893 bp. Chi-square p 1.3e-05. 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 (C>A, Δ0.26 acceptor 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): grpmax **0.00134%** (afr) · FAF95 0.000251% · FAF99 0.000161% · 1/74,428 in the highest group · 8/1,578,692 alleles overall — very rare (popmax 0.00134%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00134% | 74,428 |
| European (non-Finnish) | 0.000603% | 165,724 |

*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 **235** lies in the helicase atp-binding domain.

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.Arg235Cys falls in the helicase atp-binding domain.


### 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 2024-12-04.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2020–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-03-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-31 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-04 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [dyskeratosis congenita, autosomal recessive 5](https://sugi.bio/atlas/disease/dyskeratosis-congenita-autosomal-recessive-5/), [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](https://sugi.bio/atlas/disease/dyskeratosis-congenita/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Dyskeratosis congenita, autosomal recessive 5, Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3, Dyskeratosis congenita, 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.Arg235His](/variant/rtel1-p-arg235his), [RTEL1 p.Arg235=](/variant/rtel1-p-arg235), [RTEL1 p.Arg235Leu](/variant/rtel1-p-arg235leu), [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).

### 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 972517). 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.*