Is RTEL1 p.Pro208Arg (c.623C>G) pathogenic?

RTEL1 p.Pro208Arg (c.623C>G) is classified Uncertain significance in RTEL1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-25). AlphaMissense: likely pathogenic (0.9939); Absent from gnomAD v4.1; Associated with RTEL1-related disorder.

What condition is associated with RTEL1 p.Pro208Arg (c.623C>G)?

RTEL1 p.Pro208Arg (c.623C>G) is associated with RTEL1-related disorder (ClinVar).

How common is RTEL1 p.Pro208Arg (c.623C>G) in the general population?

RTEL1 p.Pro208Arg (c.623C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RTEL1 p.Pro208Arg (c.623C>G)?

AlphaMissense predicts likely pathogenic (score 0.9939) — an in-silico prediction, not a clinical call.

RTEL1 p.Pro208Arg

c.623C>G · VCV3350156

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9939 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RTEL1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9939	likely pathogenic · top 3% in RTEL1
REVEL	0.928	moderately pathogenic-leaning
SaProt	LLR -17.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 31 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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.Pro208Arg
Coding: c.623C>G
MANE Select: NM_001283009
Type: single nucleotide variant
Location: chr20:63667477 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB
Residue 208: the helicase atp-binding domain

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

Disease context

RTEL1-related disorder

Similar variants

RTEL1 p.Pro208Thr Uncertain significance ★ ⚠ same residue
RTEL1 p.Pro208= 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-pro208arg (accessed [today's date]).

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