Is RTEL1 p.Ala353Val (c.1058C>T) pathogenic?

RTEL1 p.Ala353Val (c.1058C>T) is classified Uncertain significance in RTEL1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-09). AlphaMissense: likely benign (0.1677); Very rare (popmax 0.0022%, nfe); Associated with Inborn genetic diseases.

How common is RTEL1 p.Ala353Val (c.1058C>T) in the general population?

RTEL1 p.Ala353Val (c.1058C>T) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about RTEL1 p.Ala353Val (c.1058C>T)?

AlphaMissense predicts likely benign (score 0.1677) — an in-silico prediction, not a clinical call.

RTEL1 p.Ala353Val

Q: What condition is associated with RTEL1 p.Ala353Val (c.1058C>T)?

RTEL1 p.Ala353Val (c.1058C>T) is associated with Inborn genetic diseases, dyskeratosis congenita, autosomal recessive 5, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (ClinVar).

c.1058C>T · rs762936013 · VCV816670

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1677 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1677	likely benign
REVEL	0.591	indeterminate
SaProt	LLR -10.18	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	26.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% European (non-Finnish) · 26/1,179,962 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00174% 28/1,611,190 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0022%	45,383
Remaining individualsnot grpmax-eligible	0.0016%	62,340
African / African-American	0.00134%	74,886

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.Ala353Val
Coding: c.1058C>T
MANE Select: NM_001283009
dbSNP: rs762936013
Type: single nucleotide variant
Location: chr20:63679869 (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.Ala353= 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-ala353val (accessed [today's date]).

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