Is RTEL1 p.Pro484Leu (c.1451C>T) pathogenic?

RTEL1 p.Pro484Leu (c.1451C>T) is classified Uncertain significance in RTEL1 (ClinVar, Single submitter, 4 submitters; last evaluated 2025-09-23). AlphaMissense: likely pathogenic (0.9123); Very rare (popmax 0.0023%, eas); Associated with dyskeratosis congenita, autosomal recessive 5.

What condition is associated with RTEL1 p.Pro484Leu (c.1451C>T)?

RTEL1 p.Pro484Leu (c.1451C>T) is associated with dyskeratosis congenita, autosomal recessive 5, pulmonary fibrosis, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (ClinVar).

How common is RTEL1 p.Pro484Leu (c.1451C>T) in the general population?

RTEL1 p.Pro484Leu (c.1451C>T) is very rare (popmax 0.0023%, eas) (gnomAD).

What do computational predictors say about RTEL1 p.Pro484Leu (c.1451C>T)?

AlphaMissense predicts likely pathogenic (score 0.9123) — an in-silico prediction, not a clinical call.

RTEL1 p.Pro484Leu

c.1451C>T · rs786205700 · VCV190473

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9123 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0023%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita, autosomal recessive 5

Computational evidence

Protein change
AlphaMissense	0.9123	likely pathogenic
REVEL	0.759	pathogenic-leaning
SaProt	LLR -15.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 31 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.0023% East Asian · 1/43,472 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000504% 8/1,585,890 alleles · very rare exomes 7/1,433,626 · genomes 1/152,264 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0023%	43,472
Admixed American	0.00179%	55,820
Remaining individualsnot grpmax-eligible	0.00163%	61,324
South Asian	0.00114%	87,772
European (non-Finnish)	0.000343%	291,902

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.Pro484Leu
Coding: c.1451C>T
MANE Select: NM_001283009
dbSNP: rs786205700
Type: single nucleotide variant
Location: chr20:63687740 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB
Residue 484: a UniProt-annotated variant site (in pfbmft3)

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

Disease context

dyskeratosis congenita, autosomal recessive 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pulmonary fibrosis pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3

Similar variants

RTEL1 p.Pro484= 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
RTEL1 c.2142-1G>C Likely pathogenic ★★ same condition
RTEL1 c.2265+1G>T Likely pathogenic ★★ same condition
RTEL1 c.2413+1G>A Likely pathogenic ★★ same condition
RTEL1 c.2413+1G>C Pathogenic/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-pro484leu (accessed [today's date]).

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