Is RTEL1 p.Pro427Ser (c.1279C>T) pathogenic?

RTEL1 p.Pro427Ser (c.1279C>T) is classified Uncertain significance in RTEL1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-12-08). AlphaMissense: likely benign (0.101); Very rare (popmax 8.48e-05%, nfe); Associated with RTEL1-related disorder.

What condition is associated with RTEL1 p.Pro427Ser (c.1279C>T)?

RTEL1 p.Pro427Ser (c.1279C>T) is associated with RTEL1-related disorder (ClinVar).

How common is RTEL1 p.Pro427Ser (c.1279C>T) in the general population?

RTEL1 p.Pro427Ser (c.1279C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RTEL1 p.Pro427Ser (c.1279C>T)?

AlphaMissense predicts likely benign (score 0.101) — an in-silico prediction, not a clinical call.

RTEL1 p.Pro427Ser

c.1279C>T · rs2517098658 · VCV3055325

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.101 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RTEL1-related disorder

Computational evidence

Protein change
AlphaMissense	0.101	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -8.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -0.083, phastCons 0.56
Regional constraint	o/e 0.86	unconstrained · MANE · 31 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	13.33	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,842 alleles

Overall 6.2e-05% 1/1,612,420 alleles · very rare exomes 1/1,460,074 · genomes 0/152,346 · 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.Pro427Ser
Coding: c.1279C>T
MANE Select: NM_001283009
dbSNP: rs2517098658
Type: single nucleotide variant
Location: chr20:63685803 (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

RTEL1-related disorder

Similar variants

RTEL1 p.Pro427Leu Uncertain significance ★ ⚠ same residue
RTEL1 p.Pro427= Likely benign ★ same residue
RTEL1 c.1596-1G>A Likely pathogenic ★★ same condition
RTEL1 p.Arg1264His Pathogenic/Likely pathogenic ★★ same condition
RTEL1 p.Arg743Ter Pathogenic/Likely pathogenic ★★ same condition
RTEL1 p.Arg872Ter Pathogenic/Likely pathogenic ★★ same condition
RTEL1 p.Glu885Ter Pathogenic/Likely pathogenic ★★ same condition
RTEL1 p.Ala1085Ser Uncertain significance ★★ ⚠ 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-pro427ser (accessed [today's date]).

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