Is RTEL1 p.Pro759= (c.2277G>A) pathogenic?

RTEL1 p.Pro759= (c.2277G>A) is classified Likely benign in RTEL1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-06). Ultra-rare (popmax 0.0165%, mid); Associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3.

How common is RTEL1 p.Pro759= (c.2277G>A) in the general population?

RTEL1 p.Pro759= (c.2277G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

RTEL1 p.Pro759=

Q: What condition is associated with RTEL1 p.Pro759= (c.2277G>A)?

RTEL1 p.Pro759= (c.2277G>A) is associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3, dyskeratosis congenita, autosomal recessive 5 (ClinVar).

c.2277G>A · rs768310963 · VCV1159482

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8	GERP -2.4
Overall
CADD	0.202	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,048 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00823%

Overall 0.00149% 24/1,605,374 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,048
South Asian	0.0165%	6,055
African / African-American	0.00268%	37,377
Remaining individualsnot grpmax-eligible	0.00161%	61,976
European (non-Finnish)	0.000426%	234,939

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.Pro759=
Coding: c.2277G>A
MANE Select: NM_001283009
dbSNP: rs768310963
Type: single nucleotide variant
Location: chr20:63690305 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB
Residue 759: the 'disordered' region

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.Pro759Ala Uncertain significance ★★ ⚠ same residue
RTEL1 p.Pro759Arg Uncertain significance ★★ ⚠ same residue
RTEL1 p.Pro759Leu Uncertain significance ★★ ⚠ same residue
RTEL1 p.Pro759Thr 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

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-pro759 (accessed [today's date]).

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