Is TERT p.Arg486Cys (c.1456C>T) pathogenic?

TERT p.Arg486Cys (c.1456C>T) is classified Conflicting classifications of pathogenicity in TERT (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-31). AlphaMissense: likely benign (0.1336); Very rare (popmax 0.00167%, amr); Associated with idiopathic pulmonary fibrosis.

What condition is associated with TERT p.Arg486Cys (c.1456C>T)?

TERT p.Arg486Cys (c.1456C>T) is associated with idiopathic pulmonary fibrosis, pulmonary fibrosis, dyskeratosis congenita, autosomal dominant 2 (ClinVar).

How common is TERT p.Arg486Cys (c.1456C>T) in the general population?

TERT p.Arg486Cys (c.1456C>T) is very rare (popmax 0.00167%, amr) (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.Arg486Cys (c.1456C>T)?

AlphaMissense predicts likely benign (score 0.1336) — an in-silico prediction, not a clinical call.

TERT p.Arg486Cys

c.1456C>T · rs199422293 · VCV39101

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1336 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

idiopathic pulmonary fibrosis

Computational evidence

Protein change
AlphaMissense	0.1336	likely benign
REVEL	0.714	pathogenic-leaning
SaProt	LLR -6.70	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 6.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.082 · regional, not allelic
Overall
CADD	24.9	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 0.00167% Admixed American · 1/59,944 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,460,056 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,944
European (non-Finnish)	0.000254%	393,247

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.Arg486Cys
Coding: c.1456C>T
MANE Select: NM_198253
dbSNP: rs199422293
Type: single nucleotide variant
Location: chr5:1293430 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.98 · 32 PDB
Residue 486: an α-helix; 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: pulmonary fibrosis dyskeratosis congenita, autosomal dominant 2 pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 dyskeratosis congenita interstitial lung disease 2

For Idiopathic pulmonary fibrosis (Orphanet):

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

Similar variants

TERT p.Arg486His Uncertain significance ★★ ⚠ same residue
TERT p.Arg486= Likely benign ★★ same residue
TERT p.Arg486Pro 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

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-arg486cys (accessed [today's date]).

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