Is RTEL1 p.Arg879Pro (c.2636G>C) pathogenic?

RTEL1 p.Arg879Pro (c.2636G>C) is classified Uncertain significance in RTEL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-08). AlphaMissense: ambiguous (0.4082); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

How common is RTEL1 p.Arg879Pro (c.2636G>C) in the general population?

RTEL1 p.Arg879Pro (c.2636G>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about RTEL1 p.Arg879Pro (c.2636G>C)?

AlphaMissense predicts ambiguous (score 0.4082) — an in-silico prediction, not a clinical call.

RTEL1 p.Arg879Pro

Q: What condition is associated with RTEL1 p.Arg879Pro (c.2636G>C)?

RTEL1 p.Arg879Pro (c.2636G>C) is associated with Inborn genetic diseases, dyskeratosis congenita, autosomal recessive 5, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (ClinVar).

c.2636G>C · rs770539835 · VCV1040625

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4082 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4082	ambiguous
REVEL	0.177	moderately benign-leaning
SaProt	LLR -9.22	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.43, phastCons 0.98
Regional constraint	o/e 1.45	unconstrained · MANE · 5,558 bp · p 3.7e-34 · regional, not allelic
Overall
CADD	21.8	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 0.000424% European (non-Finnish) · 5/1,179,738 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,611,226 alleles · very rare exomes 4/1,459,104 · genomes 1/152,122 · 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.Arg879Pro
Coding: c.2636G>C
MANE Select: NM_001283009
dbSNP: rs770539835
Type: single nucleotide variant
Location: chr20:63691821 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyskeratosis congenita, autosomal recessive 5 pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3

Similar variants

RTEL1 p.Arg879Leu Uncertain significance ★★ ⚠ same residue
RTEL1 p.Arg879Trp Uncertain significance ★★ ⚠ same residue
RTEL1 p.Arg879= Likely benign ★ same residue
RTEL1 p.Arg879fs Pathogenic/Likely pathogenic ★★ 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-arg879pro (accessed [today's date]).

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