Is RTEL1 p.Lys233Arg (c.698A>G) pathogenic?

RTEL1 p.Lys233Arg (c.698A>G) is classified Uncertain significance in RTEL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-05). AlphaMissense: likely benign (0.0926); Very rare (popmax 0.00329%, sas); Associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3.

How common is RTEL1 p.Lys233Arg (c.698A>G) in the general population?

RTEL1 p.Lys233Arg (c.698A>G) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about RTEL1 p.Lys233Arg (c.698A>G)?

AlphaMissense predicts likely benign (score 0.0926) — an in-silico prediction, not a clinical call.

RTEL1 p.Lys233Arg

Q: What condition is associated with RTEL1 p.Lys233Arg (c.698A>G)?

RTEL1 p.Lys233Arg (c.698A>G) is associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3, dyskeratosis congenita, autosomal recessive 5 (ClinVar).

c.698A>G · VCV3759707

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0926 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0926	likely benign
REVEL	0.378	indeterminate
SaProt	LLR -6.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.81	donor loss · deltas
Pangolin	Δ0.73	loss · gain 0.10 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.1	GERP 1.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 31 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	27.5	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 0.00329% South Asian · 3/91,066 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00031% 5/1,613,116 alleles · very rare exomes 4/1,460,986 · genomes 1/152,130 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,355
European (non-Finnish)	0.00017%	589,633

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.Lys233Arg
Coding: c.698A>G
MANE Select: NM_001283009
Type: single nucleotide variant
Location: chr20:63667552 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB
Residue 233: the helicase atp-binding domain

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

Disease context

pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyskeratosis congenita, autosomal recessive 5

Similar variants

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
RTEL1 c.2557-2A>G 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-lys233arg (accessed [today's date]).

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