Is TERT p.Arg669Pro (c.2006G>C) pathogenic?

TERT p.Arg669Pro (c.2006G>C) is classified Uncertain significance in TERT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely pathogenic (0.9058); Absent from gnomAD v4.1; Associated with dyskeratosis congenita, autosomal dominant 2.

What condition is associated with TERT p.Arg669Pro (c.2006G>C)?

TERT p.Arg669Pro (c.2006G>C) is associated with dyskeratosis congenita, autosomal dominant 2, idiopathic pulmonary fibrosis (ClinVar).

How common is TERT p.Arg669Pro (c.2006G>C) in the general population?

TERT p.Arg669Pro (c.2006G>C) is absent from gnomAD v4.1 (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 TERT p.Arg669Pro (c.2006G>C)?

AlphaMissense predicts likely pathogenic (score 0.9058) — an in-silico prediction, not a clinical call.

TERT p.Arg669Pro

c.2006G>C · rs1749858434 · VCV1465876

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9058 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita, autosomal dominant 2

Computational evidence

Protein change
AlphaMissense	0.9058	likely pathogenic · top 7% in TERT
REVEL	0.76	pathogenic-leaning
SaProt	LLR -15.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 1.2, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 29 kb · p 2.3e-32 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TERT
Protein: p.Arg669Pro
Coding: c.2006G>C
MANE Select: NM_198253
dbSNP: rs1749858434
Type: single nucleotide variant
Location: chr5:1279415 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.98 · 32 PDB
Residue 669: the reverse transcriptase domain; an α-helix

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

Disease context

dyskeratosis congenita, autosomal dominant 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: idiopathic pulmonary fibrosis

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

TERT p.Arg669Gln Uncertain significance ★★ ⚠ same residue
TERT p.Arg669= Likely benign ★★ same residue
TERT p.Arg669Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
TERT p.Arg669Leu Uncertain significance ★ ⚠ same residue
TERT c.2130+1G>A Likely pathogenic ★★ same condition
TERT c.2130+2T>G Likely pathogenic ★★ same condition
TERT c.2131-2A>G Likely pathogenic ★★ same condition
TERT c.2286+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/tert-p-arg669pro (accessed [today's date]).

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