Is RTEL1 p.Arg75Ser (c.225G>C) pathogenic?

RTEL1 p.Arg75Ser (c.225G>C) is classified Uncertain significance in RTEL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-08). AlphaMissense: likely benign (0.3113); Absent from gnomAD v4.1.

How common is RTEL1 p.Arg75Ser (c.225G>C) in the general population?

RTEL1 p.Arg75Ser (c.225G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RTEL1 p.Arg75Ser (c.225G>C)?

AlphaMissense predicts likely benign (score 0.3113) — an in-silico prediction, not a clinical call.

RTEL1 p.Arg75Ser

c.225G>C · rs2516992623 · VCV3253318

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3113 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3113	likely benign
REVEL	0.42	indeterminate
SaProt	LLR -7.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.47	GERP -3.2, phastCons 0.011
Regional constraint	o/e 0.86	unconstrained · MANE · 31 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	12.84	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.Arg75Ser
Coding: c.225G>C
MANE Select: NM_001283009
dbSNP: rs2516992623
Type: single nucleotide variant
Location: chr20:63661420 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB
Residue 75: the helicase atp-binding domain

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

Similar variants

RTEL1 p.Arg75Lys Uncertain significance ★ ⚠ same residue
RTEL1 p.Arg75= Likely benign ★ same residue
RTEL1 c.1037+1G>T Likely pathogenic ★★ same type
RTEL1 c.1192-2A>G Likely pathogenic ★★ same type
RTEL1 c.1596-1G>A Likely pathogenic ★★ same type
RTEL1 c.2142-1G>C Likely pathogenic ★★ same type
RTEL1 c.2265+1G>T Likely pathogenic ★★ same type
RTEL1 c.2413+1G>A Likely pathogenic ★★ same type

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-arg75ser (accessed [today's date]).

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