Is TERT p.Pro404fs (c.1195_1210dup) pathogenic?

TERT p.Pro404fs (c.11951210dup) is classified Likely pathogenic in TERT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-04). Very rare (popmax 0.000259%, nfe); Associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1.

What condition is associated with TERT p.Pro404fs (c.1195_1210dup)?

TERT p.Pro404fs (c.1195_1210dup) is associated with pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (ClinVar).

How common is TERT p.Pro404fs (c.1195_1210dup) in the general population?

TERT p.Pro404fs (c.1195_1210dup) is very rare (popmax 0.000259%, nfe) (gnomAD).

TERT p.Pro404fs

c.1195_1210dup · VCV3385331

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000259%, nfe)

Conditions

pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.4	GERP 4.2, phastCons 1
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000259% European (non-Finnish) · 3/1,158,334 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000191% 3/1,570,156 alleles · very rare exomes 2/1,417,916 · genomes 1/152,240 · joint denominator

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.Pro404fs
Coding: c.1195_1210dup
MANE Select: NM_198253
Type: Duplication
Location: chr5:1293675 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.98 · 32 PDB
Residue 404: the 'cp motif' region; the 'required for oligomerization' region; the 'rna-interacting domain 2' region; the 'qfp motif' region

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

Disease context

pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TERT c.2655-47_2659dup Uncertain significance ★★ same condition
TERT p.Pro404Ala Uncertain significance ★★ ⚠ same residue
TERT p.Pro404Arg Uncertain significance ★★ ⚠ same residue
TERT p.Pro404Leu Uncertain significance ★★ ⚠ same residue
TERT p.Pro404Ser Uncertain significance ★ ⚠ same residue
TERT c.2131-2A>G Likely pathogenic ★★ same condition
TERT p.Ala1009Val Likely pathogenic ★★ same condition
TERT p.Ala716Thr Pathogenic/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-pro404fs (accessed [today's date]).

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