# NM_001283009.2(RTEL1):c.3381C>T (p.Arg1127=)

https://sugi.bio/variant/rtel1-p-arg1127

## Summary

**RTEL1 p.Arg1127= (c.3381C>T)** is classified **Conflicting classifications of pathogenicity** in RTEL1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-15). Very rare (popmax 0.00119%, nfe); Associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs368588082 · 3 submitters · 2 linked conditions · very rare (popmax 0.00119%, nfe)

## For patients & families {#patients}

This is a change in the RTEL1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 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.Arg1127= |
| Coding change (HGVS c.) | c.3381C>T |
| MANE Select transcript | [NM_001283009](https://www.ncbi.nlm.nih.gov/nuccore/NM_001283009) |
| dbSNP | [rs368588082](https://www.ncbi.nlm.nih.gov/snp/rs368588082/) |
| Variant type | single nucleotide variant |
| Location | chr20:63695103-63695103 (GRCh38) |
| ClinVar | [VCV436578](https://www.ncbi.nlm.nih.gov/clinvar/variation/436578/) |

**All HGVS expressions:** `LRG_1149:g.42294C>T`, `LRG_1149t1:c.3453C>T`, `LRG_1149t2:c.3381C>T`, `LRG_1149t3:c.3381C>T`, `NC_000020.10:g.62326456C>T`, `NC_000020.11:g.63695103C>T`, `NG_033901.1:g.42294C>T`, `NG_046961.1:g.3453C>T`, `NM_001283009.2:c.3381C>T`, `NM_001283010.1:c.2712C>T`, `NM_016434.4:c.3381C>T`, `NM_032957.5:c.3453C>T`, `NR_037882.1:n.4208C>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.39) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.48, GERP -2.86 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 15.46**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.05**, donor loss **0.00**, acceptor gain **0.39**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.05**, donor loss **0.00**, acceptor gain **0.39**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00119%** (nfe) · FAF95 0.000689% · FAF99 0.000539% · 14/1,179,870 in the highest group · 14/1,612,428 alleles overall — very rare (popmax 0.00119%, 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 **1127** lies in an α-helix.

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-15.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2015–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-08-26 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-11-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-15 |

## 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, not specified, Dyskeratosis congenita, autosomal recessive 5, RTEL1-related disorder, AllHighlyPenetrant, RTEL1-related condition, RTEL1-related disorders, 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.Arg1127Cys](/variant/rtel1-p-arg1127cys), [RTEL1 p.Arg1127His](/variant/rtel1-p-arg1127his), [RTEL1 p.Arg1127Gly](/variant/rtel1-p-arg1127gly), [RTEL1 p.Arg1127Ser](/variant/rtel1-p-arg1127ser), [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).

### 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 436578). 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.*