Is RTEL1 p.Val708Ile (c.2122G>A) pathogenic?

RTEL1 p.Val708Ile (c.2122G>A) is classified Likely benign in RTEL1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-03-03). AlphaMissense: likely benign (0.0616); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RTEL1 p.Val708Ile (c.2122G>A)?

RTEL1 p.Val708Ile (c.2122G>A) is associated with Inborn genetic diseases, dyskeratosis congenita (ClinVar).

How common is RTEL1 p.Val708Ile (c.2122G>A) in the general population?

RTEL1 p.Val708Ile (c.2122G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RTEL1 p.Val708Ile (c.2122G>A)?

AlphaMissense predicts likely benign (score 0.0616) — an in-silico prediction, not a clinical call.

RTEL1 p.Val708Ile

c.2122G>A · VCV3791197

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0616 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0616	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -4.97	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 0.49	GERP -2.4, phastCons 0.007
Regional constraint	o/e 0.86	unconstrained · MANE · 31 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	5.865	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 8.48e-05% European (non-Finnish) · 1/1,179,736 alleles

Overall 6.21e-05% 1/1,609,956 alleles · very rare exomes 1/1,457,634 · genomes 0/152,322 · joint denominator

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.Val708Ile
Coding: c.2122G>A
MANE Select: NM_001283009
Type: single nucleotide variant
Location: chr20:63689846 (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

Similar variants

RTEL1 p.Val708= Likely benign ★ same residue
RTEL1 c.1037+1G>T Likely pathogenic ★★ same condition
RTEL1 c.2265+1G>T Likely pathogenic ★★ same condition
RTEL1 c.2413+1G>C Pathogenic/Likely pathogenic ★★ same condition
RTEL1 c.3110-2A>C Likely pathogenic ★★ same condition
RTEL1 c.3110-2A>T Pathogenic/Likely pathogenic ★★ same condition
RTEL1 c.396-26C>T Pathogenic/Likely pathogenic ★★ same condition
RTEL1 p.Arg1264His 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-val708ile (accessed [today's date]).

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