Is RTEL1 p.Lys19Arg (c.56A>G) pathogenic?

RTEL1 p.Lys19Arg (c.56A>G) is classified Uncertain significance in RTEL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-26). AlphaMissense: likely benign (0.0655); Very rare (popmax 0.00223%, eas); Associated with dyskeratosis congenita, autosomal recessive 5.

What condition is associated with RTEL1 p.Lys19Arg (c.56A>G)?

RTEL1 p.Lys19Arg (c.56A>G) is associated with dyskeratosis congenita, autosomal recessive 5, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (ClinVar).

How common is RTEL1 p.Lys19Arg (c.56A>G) in the general population?

RTEL1 p.Lys19Arg (c.56A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about RTEL1 p.Lys19Arg (c.56A>G)?

AlphaMissense predicts likely benign (score 0.0655) — an in-silico prediction, not a clinical call.

RTEL1 p.Lys19Arg

c.56A>G · rs2146141516 · VCV1422913

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita, autosomal recessive 5

Computational evidence

Protein change
AlphaMissense	0.0655	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -5.64	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.41	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -0.61	GERP -0.98
Regional constraint	o/e 0.86	unconstrained · MANE · 31 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	10.93	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,872 alleles

Overall 6.2e-05% 1/1,614,174 alleles · very rare exomes 1/1,461,862 · genomes 0/152,312 · 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.Lys19Arg
Coding: c.56A>G
MANE Select: NM_001283009
dbSNP: rs2146141516
Type: single nucleotide variant
Location: chr20:63659458 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB
Residue 19: the helicase atp-binding domain

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

Disease context

dyskeratosis congenita, autosomal recessive 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3

Similar variants

RTEL1 p.Lys19Glu Uncertain significance ★ ⚠ same residue
RTEL1 c.1037+1G>T Likely pathogenic ★★ same condition
RTEL1 c.1192-2A>G Likely pathogenic ★★ same condition
RTEL1 c.1596-1G>A Likely pathogenic ★★ same condition
RTEL1 c.2142-1G>C Likely pathogenic ★★ same condition
RTEL1 c.2265+1G>T Likely pathogenic ★★ same condition
RTEL1 c.2413+1G>A Likely pathogenic ★★ same condition
RTEL1 c.2413+1G>C 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-lys19arg (accessed [today's date]).

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