Is RTEL1 p.Val247Met (c.739G>A) pathogenic?

RTEL1 p.Val247Met (c.739G>A) is classified Uncertain significance in RTEL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-27). AlphaMissense: ambiguous (0.458); Very rare (popmax 0.00226%, eas); Associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3.

How common is RTEL1 p.Val247Met (c.739G>A) in the general population?

RTEL1 p.Val247Met (c.739G>A) is very rare (popmax 0.00226%, eas) (gnomAD).

What do computational predictors say about RTEL1 p.Val247Met (c.739G>A)?

AlphaMissense predicts ambiguous (score 0.458) — an in-silico prediction, not a clinical call.

RTEL1 p.Val247Met

Q: What condition is associated with RTEL1 p.Val247Met (c.739G>A)?

RTEL1 p.Val247Met (c.739G>A) is associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3, dyskeratosis congenita, autosomal recessive 5 (ClinVar).

c.739G>A · rs1194320122 · VCV944426

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.458 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00226%, eas)

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.458	ambiguous
REVEL	0.452	indeterminate
SaProt	LLR -12.49	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 31 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00226% East Asian · 1/44,248 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000315% 5/1,587,294 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00226%	44,248
Remaining individualsnot grpmax-eligible	0.00163%	61,514
European (non-Finnish)	0.000258%	388,273

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.Val247Met
Coding: c.739G>A
MANE Select: NM_001283009
dbSNP: rs1194320122
Type: single nucleotide variant
Location: chr20:63672595 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB
Residue 247: 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 p.Val247= Likely benign ★ 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-val247met (accessed [today's date]).

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