Is RTEL1 p.Leu799Pro (c.2396T>C) pathogenic?

RTEL1 p.Leu799Pro (c.2396T>C) is classified Uncertain significance in RTEL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-15). AlphaMissense: likely pathogenic (0.6039); Very rare (popmax 0.00814%, afr); Associated with dyskeratosis congenita, autosomal recessive 5.

What condition is associated with RTEL1 p.Leu799Pro (c.2396T>C)?

RTEL1 p.Leu799Pro (c.2396T>C) is associated with dyskeratosis congenita, autosomal recessive 5, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (ClinVar).

How common is RTEL1 p.Leu799Pro (c.2396T>C) in the general population?

RTEL1 p.Leu799Pro (c.2396T>C) is very rare (popmax 0.00814%, afr) (gnomAD).

What do computational predictors say about RTEL1 p.Leu799Pro (c.2396T>C)?

AlphaMissense predicts likely pathogenic (score 0.6039) — an in-silico prediction, not a clinical call.

RTEL1 p.Leu799Pro

c.2396T>C · VCV4785713

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6039 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00814%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita, autosomal recessive 5

Computational evidence

Protein change
AlphaMissense	0.6039	likely pathogenic
REVEL	0.144	moderately benign-leaning
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Regional constraint	o/e 1.45	unconstrained · MANE · 5,558 bp · p 3.7e-34 · regional, not allelic
Overall
CADD	25.0	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 0.00814% African / African-American · 6/73,754 alleles

Filtering AF 0.00352% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000438% 7/1,596,812 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00814%	12,292
Remaining individualsnot grpmax-eligible	0.00162%	61,660

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.Leu799Pro
Coding: c.2396T>C
MANE Select: NM_001283009
Type: single nucleotide variant
Location: chr20:63690424 (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

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

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

Similar variants

RTEL1 p.Leu799Val Uncertain significance ★ ⚠ same residue
RTEL1 p.Leu799= 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

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-leu799pro (accessed [today's date]).

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