Is RTEL1 p.Pro1254Arg (c.3761C>G) pathogenic?

RTEL1 p.Pro1254Arg (c.3761C>G) is classified Uncertain significance in RTEL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-12). Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RTEL1 p.Pro1254Arg (c.3761C>G)?

RTEL1 p.Pro1254Arg (c.3761C>G) is associated with Inborn genetic diseases (ClinVar).

How common is RTEL1 p.Pro1254Arg (c.3761C>G) in the general population?

RTEL1 p.Pro1254Arg (c.3761C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

RTEL1 p.Pro1254Arg

c.3761C>G · VCV3790958

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

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

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.244	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.44	GERP -2.8, phastCons 0.15
Regional constraint	o/e 1.45	unconstrained · MANE · 5,558 bp · p 3.7e-34 · regional, not allelic
Overall
CADD	11.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,900 alleles

Overall 0.000124% 2/1,612,090 alleles · very rare exomes 2/1,459,772 · genomes 0/152,318 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,468
European (non-Finnish)grpmax	8.48e-05%	1,179,901

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1254Arg
Coding: c.3761C>G
MANE Select: NM_001283009
Type: single nucleotide variant
Location: chr20:63695589 (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.Pro1254= Likely benign ★★ same residue
RTEL1 p.Pro1254Ala Uncertain significance ★ same residue
RTEL1 p.Pro1254Leu Conflicting classifications of pathogenicity ★ same residue
RTEL1 p.Pro1254Ser Likely benign ★ same residue
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

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-pro1254arg (accessed [today's date]).

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