Is RTEL1 p.Ala760Val (c.2279C>T) pathogenic?

RTEL1 p.Ala760Val (c.2279C>T) is classified Uncertain significance in RTEL1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-26). AlphaMissense: likely benign (0.0663); Ultra-rare (popmax 0.0143%, sas); Associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3.

What condition is associated with RTEL1 p.Ala760Val (c.2279C>T)?

RTEL1 p.Ala760Val (c.2279C>T) 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.Ala760Val (c.2279C>T) in the general population?

RTEL1 p.Ala760Val (c.2279C>T) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about RTEL1 p.Ala760Val (c.2279C>T)?

AlphaMissense predicts likely benign (score 0.0663) — an in-silico prediction, not a clinical call.

RTEL1 p.Ala760Val

c.2279C>T · rs761666401 · VCV1692615

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0663 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0663	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -6.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.8	GERP -2.4
Regional constraint	o/e 1.45	unconstrained · MANE · 5,558 bp · p 3.7e-34 · regional, not allelic
Overall
CADD	0.612	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 0.0143% South Asian · 13/90,620 alleles

Filtering AF 0.00848% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00664%

Overall 0.00117% 17/1,449,396 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	6,971
European (non-Finnish)	0.000341%	292,900

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.Ala760Val
Coding: c.2279C>T
MANE Select: NM_001283009
dbSNP: rs761666401
Type: single nucleotide variant
Location: chr20:63690307 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB
Residue 760: the 'disordered' region

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.Ala760Pro Uncertain significance ★★ ⚠ same residue
RTEL1 p.Ala760= Likely benign ★★ same residue
RTEL1 p.Ala760Ser 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

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-ala760val (accessed [today's date]).

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