Is RTEL1 p.Ser594Arg (c.1782C>G) pathogenic?

RTEL1 p.Ser594Arg (c.1782C>G) is classified Uncertain significance in RTEL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-03-12). AlphaMissense: ambiguous (0.5448); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with RTEL1 p.Ser594Arg (c.1782C>G)?

RTEL1 p.Ser594Arg (c.1782C>G) is associated with Inborn genetic diseases (ClinVar).

How common is RTEL1 p.Ser594Arg (c.1782C>G) in the general population?

RTEL1 p.Ser594Arg (c.1782C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RTEL1 p.Ser594Arg (c.1782C>G)?

AlphaMissense predicts ambiguous (score 0.5448) — an in-silico prediction, not a clinical call.

RTEL1 p.Ser594Arg

c.1782C>G · VCV4827719

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5448 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5448	ambiguous
REVEL	0.194	benign-leaning
SaProt	LLR -8.68	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 2.1	GERP 0.51, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 31 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	21.6	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

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.Ser594Arg
Coding: c.1782C>G
MANE Select: NM_001283009
Type: single nucleotide variant
Location: chr20:63688587 (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

Similar variants

RTEL1 p.Ala1012Ser Uncertain significance ★★ ⚠ same condition
RTEL1 p.Ala1052Thr Uncertain significance ★★ ⚠ same condition
RTEL1 p.Ala1074Val Uncertain significance ★★ ⚠ same condition
RTEL1 p.Ala1085Val Uncertain significance ★★ ⚠ same condition
RTEL1 p.Ala1101Thr Uncertain significance ★★ ⚠ same condition
RTEL1 p.Ala112Val Uncertain significance ★★ ⚠ same condition
RTEL1 p.Ala1240Pro Uncertain significance ★★ same condition
RTEL1 p.Ala1275Ser 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-ser594arg (accessed [today's date]).

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