Is RTEL1 p.Arg986fs (c.2956del) pathogenic?

RTEL1 p.Arg986fs (c.2956del) is classified Pathogenic/Likely pathogenic in RTEL1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-01). Very rare (popmax 6.2e-05%); Associated with Autosomal dominant RTEL1-related disorders.

What condition is associated with RTEL1 p.Arg986fs (c.2956del)?

RTEL1 p.Arg986fs (c.2956del) is associated with Autosomal dominant RTEL1-related disorders, dyskeratosis congenita, autosomal recessive 5, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (ClinVar).

How common is RTEL1 p.Arg986fs (c.2956del) in the general population?

RTEL1 p.Arg986fs (c.2956del) is very rare (popmax 6.2e-05%) (gnomAD).

RTEL1 p.Arg986fs

c.2956del · rs1285014916 · VCV548700

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Conditions

Autosomal dominant RTEL1-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 30 of 35
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.52	GERP 0.56
Overall
CADD	17.05	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,611,906 alleles · very rare exomes 0/1,459,868 · genomes 1/152,038 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RTEL1
Protein: p.Arg986fs
Coding: c.2956del
MANE Select: NM_001283009
dbSNP: rs1285014916
Type: Deletion
Location: chr20:63693244 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB
Residue 986: the 'disordered' region

Full RTEL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Autosomal dominant RTEL1-related disorders

Also linked: dyskeratosis congenita, autosomal recessive 5 pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3

Similar variants

RTEL1 p.Arg986= Likely benign ★★ same residue
RTEL1 p.Arg986Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
RTEL1 p.Arg986Leu Uncertain significance ★ ⚠ same residue
RTEL1 c.1236_1266+47del Pathogenic/Likely pathogenic ★★ same condition
RTEL1 p.Arg733fs Pathogenic/Likely pathogenic ★★ same condition
RTEL1 p.Arg879fs Pathogenic/Likely pathogenic ★★ same condition
RTEL1 p.Asn637fs Pathogenic/Likely pathogenic ★★ same condition
RTEL1 p.Gln1187fs Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rtel1-p-arg986fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown