Is RTEL1 p.Cys968Ser (c.2903G>C) pathogenic?

RTEL1 p.Cys968Ser (c.2903G>C) is classified Uncertain significance in RTEL1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-15). AlphaMissense: likely pathogenic (0.6875); Ultra-rare (popmax 0.0263%, sas); Associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3.

What condition is associated with RTEL1 p.Cys968Ser (c.2903G>C)?

RTEL1 p.Cys968Ser (c.2903G>C) 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.Cys968Ser (c.2903G>C) in the general population?

RTEL1 p.Cys968Ser (c.2903G>C) is ultra-rare (popmax 0.0263%, sas) (gnomAD).

What do computational predictors say about RTEL1 p.Cys968Ser (c.2903G>C)?

AlphaMissense predicts likely pathogenic (score 0.6875) — an in-silico prediction, not a clinical call.

RTEL1 p.Cys968Ser

c.2903G>C · rs375503989 · VCV967384

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6875 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0263%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.6875	likely pathogenic
REVEL	0.399	indeterminate
SaProt	LLR -9.68	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.45	unconstrained · MANE · 5,558 bp · p 3.7e-34 · regional, not allelic
Overall
CADD	24.7	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 0.0263% South Asian · 24/91,092 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00304% 49/1,612,174 alleles · ultra-rare exomes 48/1,459,966 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0263%	3,795
European (non-Finnish)	0.00203%	49,147
Admixed American	0.00167%	59,986

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.Cys968Ser
Coding: c.2903G>C
MANE Select: NM_001283009
dbSNP: rs375503989
Type: single nucleotide variant
Location: chr20:63693194 (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

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.Cys968= Likely benign ★★ same residue
RTEL1 p.Cys968Phe Uncertain significance ★ same residue
RTEL1 p.Cys968Trp 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-cys968ser (accessed [today's date]).

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