Is RTEL1 p.Pro1237Ser (c.3709C>T) pathogenic?

RTEL1 p.Pro1237Ser (c.3709C>T) is classified Uncertain significance in RTEL1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-15). Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

How common is RTEL1 p.Pro1237Ser (c.3709C>T) in the general population?

RTEL1 p.Pro1237Ser (c.3709C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

RTEL1 p.Pro1237Ser

Q: What condition is associated with RTEL1 p.Pro1237Ser (c.3709C>T)?

RTEL1 p.Pro1237Ser (c.3709C>T) is associated with Inborn genetic diseases, dyskeratosis congenita, autosomal recessive 5, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (ClinVar).

c.3709C>T · rs1455414990 · VCV2139227

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.243	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.9, phastCons 0.019
Regional constraint	o/e 1.45	unconstrained · MANE · 5,558 bp · p 3.7e-34 · regional, not allelic
Overall
CADD	13.68	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,864 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,612,240 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,864
European (non-Finnish)	0.000339%	294,958

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.Pro1237Ser
Coding: c.3709C>T
MANE Select: NM_001283009
dbSNP: rs1455414990
Type: single nucleotide variant
Location: chr20:63695537 (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

Also linked: dyskeratosis congenita, autosomal recessive 5 pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3

Similar variants

RTEL1 p.Pro1237= Likely benign ★★ same residue
RTEL1 p.Pro1237His Uncertain significance ★ same residue
RTEL1 p.Pro1237Leu Uncertain significance ★ same residue
RTEL1 p.Pro1237Thr Uncertain significance ★ same residue
RTEL1 p.Pro1237Ala Likely benign ★ same residue
RTEL1 c.1037+1G>T Likely pathogenic ★★ same condition
RTEL1 c.1192-2A>G Likely pathogenic ★★ same condition
RTEL1 c.1596-1G>A Likely pathogenic ★★ 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-pro1237ser (accessed [today's date]).

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