Is RTEL1 p.Val255Met (c.763G>A) pathogenic?

RTEL1 p.Val255Met (c.763G>A) is classified Uncertain significance in RTEL1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-08-24). AlphaMissense: likely benign (0.3336); Ultra-rare (popmax 0.0166%, mid); Associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3.

What condition is associated with RTEL1 p.Val255Met (c.763G>A)?

RTEL1 p.Val255Met (c.763G>A) is associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3, dyskeratosis congenita, autosomal recessive 5, dyskeratosis congenita (ClinVar).

How common is RTEL1 p.Val255Met (c.763G>A) in the general population?

RTEL1 p.Val255Met (c.763G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about RTEL1 p.Val255Met (c.763G>A)?

AlphaMissense predicts likely benign (score 0.3336) — an in-silico prediction, not a clinical call.

RTEL1 p.Val255Met

c.763G>A · rs778675789 · VCV840820

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.3336 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.3336	likely benign
REVEL	0.532	indeterminate
SaProt	LLR -9.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP -0.22, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 31 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0166% Middle Eastern · 1/6,036 alleles

Filtering AF 0.00519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00476%

Overall 0.00519% 82/1,581,318 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,036
European (non-Finnish)	0.00637%	15,691
South Asian	0.00346%	28,932
Ashkenazi Jewishnot grpmax-eligible	0.00345%	29,026
Remaining individualsnot grpmax-eligible	0.00327%	30,625
African / African-American	0.00134%	74,524

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.Val255Met
Coding: c.763G>A
MANE Select: NM_001283009
dbSNP: rs778675789
Type: single nucleotide variant
Location: chr20:63672619 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB
Residue 255: the helicase atp-binding domain

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

Disease context

pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyskeratosis congenita, autosomal recessive 5 dyskeratosis congenita

Similar variants

RTEL1 p.Val255Leu Uncertain significance ★ ⚠ 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-val255met (accessed [today's date]).

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