Is RTEL1 p.Arg235His (c.704G>A) pathogenic?

RTEL1 p.Arg235His (c.704G>A) is classified Uncertain significance in RTEL1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-27). AlphaMissense: likely pathogenic (0.6895); Very rare (popmax 0.00228%, eas); Associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3.

What condition is associated with RTEL1 p.Arg235His (c.704G>A)?

RTEL1 p.Arg235His (c.704G>A) is associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3, pulmonary fibrosis, dyskeratosis congenita, autosomal recessive 5 (ClinVar).

How common is RTEL1 p.Arg235His (c.704G>A) in the general population?

RTEL1 p.Arg235His (c.704G>A) is very rare (popmax 0.00228%, eas) (gnomAD).

What do computational predictors say about RTEL1 p.Arg235His (c.704G>A)?

AlphaMissense predicts likely pathogenic (score 0.6895) — an in-silico prediction, not a clinical call.

RTEL1 p.Arg235His

c.704G>A · rs549397879 · VCV1163653

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00228%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.6895	likely pathogenic
REVEL	0.669	pathogenic-leaning
SaProt	LLR -14.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP -0.13, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 31 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00228% East Asian · 1/43,818 alleles

Filtering AF 0.000126% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.2e-05%

Overall 0.00042% 6/1,426,956 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00228%	43,818
European (non-Finnish)	0.000431%	232,070

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.Arg235His
Coding: c.704G>A
MANE Select: NM_001283009
dbSNP: rs549397879
Type: single nucleotide variant
Location: chr20:63672560 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB
Residue 235: 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: pulmonary fibrosis dyskeratosis congenita, autosomal recessive 5

Similar variants

RTEL1 p.Arg235Cys Uncertain significance ★★ ⚠ same residue
RTEL1 p.Arg235= Likely benign ★★ same residue
RTEL1 p.Arg235Leu 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

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-arg235his (accessed [today's date]).

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