Is TERT p.Pro704Ser (c.2110C>T) pathogenic?

TERT p.Pro704Ser (c.2110C>T) is classified Pathogenic/Likely pathogenic in TERT (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-11-17). AlphaMissense: likely benign (0.1022); Very rare (popmax 0.00135%, afr); Associated with idiopathic pulmonary fibrosis.

What condition is associated with TERT p.Pro704Ser (c.2110C>T)?

TERT p.Pro704Ser (c.2110C>T) is associated with idiopathic pulmonary fibrosis, pulmonary fibrosis, dyskeratosis congenita, autosomal dominant 1 (ClinVar).

How common is TERT p.Pro704Ser (c.2110C>T) in the general population?

TERT p.Pro704Ser (c.2110C>T) is very rare (popmax 0.00135%, afr) (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.Pro704Ser (c.2110C>T)?

AlphaMissense predicts likely benign (score 0.1022) — an in-silico prediction, not a clinical call.

TERT p.Pro704Ser

c.2110C>T · rs199422297 · VCV39108

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1022 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

idiopathic pulmonary fibrosis

Computational evidence

Protein change
AlphaMissense	0.1022	likely benign ⚠ discordant with ClinVar
REVEL	0.619	indeterminate
SaProt	LLR -12.12	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -2.5, phastCons 0.91
Regional constraint	o/e 0.58	unconstrained · MANE · 29 kb · p 2.3e-32 · regional, not allelic
Overall
CADD	13.66	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 0.00135% African / African-American · 1/74,322 alleles

Filtering AF 0.000621% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000479%

Overall 0.000884% 14/1,584,006 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	74,322
European (non-Finnish)	0.00111%	89,807

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.Pro704Ser
Coding: c.2110C>T
MANE Select: NM_198253
dbSNP: rs199422297
Type: single nucleotide variant
Location: chr5:1279311 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.98 · 32 PDB
Residue 704: the reverse transcriptase domain; an α-helix; a UniProt-annotated variant site (in dkcb4; the mutant protein has 13% residual activity)

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: pulmonary fibrosis dyskeratosis congenita, autosomal dominant 1 dyskeratosis congenita, autosomal dominant 2 pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 dyskeratosis congenita autosomal recessive dyskeratosis congenita 4

For Idiopathic pulmonary fibrosis (Orphanet):

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

Similar variants

TERT p.Pro704= Likely benign ★★ 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
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-pro704ser (accessed [today's date]).

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