Is RTEL1 p.Pro996His (c.2987C>A) pathogenic?

RTEL1 p.Pro996His (c.2987C>A) is classified Conflicting classifications of pathogenicity in RTEL1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0934); Rare (popmax 0.194%, eas); Associated with dyskeratosis congenita.

How common is RTEL1 p.Pro996His (c.2987C>A) in the general population?

RTEL1 p.Pro996His (c.2987C>A) is rare (popmax 0.194%, eas) (gnomAD).

How is Dyskeratosis congenita inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RTEL1 p.Pro996His (c.2987C>A)?

AlphaMissense predicts likely benign (score 0.0934) — an in-silico prediction, not a clinical call.

RTEL1 p.Pro996His

Q: What condition is associated with RTEL1 p.Pro996His (c.2987C>A)?

RTEL1 p.Pro996His (c.2987C>A) is associated with dyskeratosis congenita, dyskeratosis congenita, autosomal recessive 5, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (ClinVar).

c.2987C>A · rs373210484 · VCV436594

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0934 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.194%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.0934	likely benign
REVEL	0.161	moderately benign-leaning
SaProt	LLR -7.57	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 0.7	GERP -1.2
Regional constraint	o/e 1.45	unconstrained · MANE · 5,558 bp · p 3.7e-34 · regional, not allelic
Overall
CADD	8.776	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 0.194% East Asian · 87/44,888 alleles

Filtering AF 0.161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.149%

Overall 0.0115% 186/1,611,674 alleles · rare exomes 162/1,459,532 · genomes 24/152,142 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.194%	516
Remaining individualsnot grpmax-eligible	0.123%	811
Admixed American	0.00667%	14,987
European (non-Finnish)	0.00153%	65,520

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.Pro996His
Coding: c.2987C>A
MANE Select: NM_001283009
dbSNP: rs373210484
Type: single nucleotide variant
Location: chr20:63693278 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.64 · 3 PDB
Residue 996: the 'disordered' region

Full RTEL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dyskeratosis congenita — 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

For Dyskeratosis congenita (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

RTEL1 p.Pro996= Likely benign ★★ same residue
RTEL1 p.Pro996Arg Uncertain significance ★ ⚠ same residue
RTEL1 p.Pro996Leu Uncertain significance ★ ⚠ same residue
RTEL1 p.Pro996Ala Uncertain significance ★★ ⚠ same residue
RTEL1 p.Pro996Ser Uncertain significance ★★ ⚠ same residue
RTEL1 p.Pro996Thr Uncertain significance ★ ⚠ same residue
RTEL1 c.1037+1G>T Likely pathogenic ★★ same condition
RTEL1 c.1192-2A>G 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-pro996his (accessed [today's date]).

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