Is TERT p.Arg669Trp (c.2005C>T) pathogenic?

TERT p.Arg669Trp (c.2005C>T) is classified Conflicting classifications of pathogenicity in TERT (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-03-12). AlphaMissense: likely benign (0.2692); Very rare (popmax 0.00148%, nfe); Associated with acute myeloid leukemia.

How common is TERT p.Arg669Trp (c.2005C>T) in the general population?

TERT p.Arg669Trp (c.2005C>T) is very rare (popmax 0.00148%, nfe) (gnomAD).

What do computational predictors say about TERT p.Arg669Trp (c.2005C>T)?

AlphaMissense predicts likely benign (score 0.2692) — an in-silico prediction, not a clinical call.

TERT p.Arg669Trp

Q: What condition is associated with TERT p.Arg669Trp (c.2005C>T)?

TERT p.Arg669Trp (c.2005C>T) is associated with acute myeloid leukemia, dyskeratosis congenita, autosomal dominant 2, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (ClinVar).

c.2005C>T · rs372140951 · VCV539196

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2692 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00148%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acute myeloid leukemia

Computational evidence

Protein change
AlphaMissense	0.2692	likely benign
REVEL	0.718	pathogenic-leaning
SaProt	LLR -12.18	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 29 kb · p 2.3e-32 · regional, not allelic
Overall
CADD	21.3	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 0.00148% European (non-Finnish) · 17/1,148,834 alleles

Filtering AF 0.000901% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000737%

Overall 0.00116% 18/1,551,682 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0017%	58,658
European (non-Finnish)grpmax	0.00148%	67,579

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TERT
Protein: p.Arg669Trp
Coding: c.2005C>T
MANE Select: NM_198253
dbSNP: rs372140951
Type: single nucleotide variant
Location: chr5:1279416 (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

acute myeloid leukemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyskeratosis congenita, autosomal dominant 2 pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 melanoma, cutaneous malignant, susceptibility to, 9 dyskeratosis congenita idiopathic pulmonary fibrosis

Similar variants

TERT p.Arg669Gln Uncertain significance ★★ ⚠ same residue
TERT p.Arg669= Likely benign ★★ same residue
TERT p.Arg669Leu Uncertain significance ★ ⚠ same residue
TERT p.Arg669Pro 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-arg669trp (accessed [today's date]).

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