Is RTEL1 p.Pro1139Ala (c.3415C>G) pathogenic?

RTEL1 p.Pro1139Ala (c.3415C>G) is classified Uncertain significance in RTEL1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.0648); Absent from gnomAD v4.1; Associated with dyskeratosis congenita.

What condition is associated with RTEL1 p.Pro1139Ala (c.3415C>G)?

RTEL1 p.Pro1139Ala (c.3415C>G) is associated with dyskeratosis congenita (ClinVar).

How common is RTEL1 p.Pro1139Ala (c.3415C>G) in the general population?

RTEL1 p.Pro1139Ala (c.3415C>G) is absent from gnomAD v4.1 (gnomAD).

How is Dyskeratosis congenita inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RTEL1 p.Pro1139Ala (c.3415C>G)?

AlphaMissense predicts likely benign (score 0.0648) — an in-silico prediction, not a clinical call.

RTEL1 p.Pro1139Ala

c.3415C>G · VCV4060923

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0648 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.0648	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -7.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.42	GERP 1.3, phastCons 0.01
Regional constraint	o/e 1.45	unconstrained · MANE · 5,558 bp · p 3.7e-34 · regional, not allelic
Overall
CADD	5.865	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RTEL1
Protein: p.Pro1139Ala
Coding: c.3415C>G
MANE Select: NM_001283009
Type: single nucleotide variant
Location: chr20:63695137 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB
Residue 1139: the 'disordered' region

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

Disease context

dyskeratosis congenita — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dyskeratosis congenita (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

RTEL1 p.Pro1139Leu Uncertain significance ★★ ⚠ same residue
RTEL1 p.Pro1139= Likely benign ★ same residue
RTEL1 c.1037+1G>T Likely pathogenic ★★ same condition
RTEL1 c.2265+1G>T Likely pathogenic ★★ same condition
RTEL1 c.2413+1G>C Pathogenic/Likely pathogenic ★★ same condition
RTEL1 c.3110-2A>C Likely pathogenic ★★ same condition
RTEL1 c.3110-2A>T Pathogenic/Likely pathogenic ★★ same condition
RTEL1 c.396-26C>T 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-pro1139ala (accessed [today's date]).

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