Is TERT p.Pro414Ser (c.1240C>T) pathogenic?

TERT p.Pro414Ser (c.1240C>T) is classified Uncertain significance in TERT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-15). AlphaMissense: likely benign (0.1669); Very rare (popmax 0.00118%, sas); Associated with idiopathic pulmonary fibrosis.

What condition is associated with TERT p.Pro414Ser (c.1240C>T)?

TERT p.Pro414Ser (c.1240C>T) is associated with idiopathic pulmonary fibrosis, dyskeratosis congenita, autosomal dominant 2 (ClinVar).

How common is TERT p.Pro414Ser (c.1240C>T) in the general population?

TERT p.Pro414Ser (c.1240C>T) is very rare (popmax 0.00118%, sas) (gnomAD).

How is Idiopathic pulmonary fibrosis inherited?

Typically Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TERT p.Pro414Ser (c.1240C>T)?

AlphaMissense predicts likely benign (score 0.1669) — an in-silico prediction, not a clinical call.

TERT p.Pro414Ser

c.1240C>T · rs2126685248 · VCV1449796

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00118%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

idiopathic pulmonary fibrosis

Computational evidence

Protein change
AlphaMissense	0.1669	likely benign
REVEL	0.557	indeterminate
SaProt	LLR -10.70	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.1	GERP 4.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.082 · regional, not allelic
Overall
CADD	23.8	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 0.00118% South Asian · 1/84,742 alleles

Overall 6.41e-05% 1/1,559,494 alleles · very rare exomes 1/1,407,132 · genomes 0/152,362 · 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.Pro414Ser
Coding: c.1240C>T
MANE Select: NM_198253
dbSNP: rs2126685248
Type: single nucleotide variant
Location: chr5:1293646 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.98 · 32 PDB
Residue 414: 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

idiopathic pulmonary fibrosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyskeratosis congenita, autosomal dominant 2

For Idiopathic pulmonary fibrosis (Orphanet):

Inheritance: Multigenic/multifactorial
Onset: Adult
Prevalence: 1-5 / 10 000 (Worldwide)

Similar variants

TERT p.Pro414= Likely benign ★★ same residue
TERT p.Pro414Leu 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
TERT c.3157+1G>T Likely pathogenic ★★ same condition
TERT p.Ala1009Val 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-pro414ser (accessed [today's date]).

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