Is TERT p.Arg577Trp (c.1729C>T) pathogenic?

TERT p.Arg577Trp (c.1729C>T) is classified Conflicting classifications of pathogenicity in TERT (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-17). AlphaMissense: likely pathogenic (0.6018); Very rare (popmax 0.00223%, eas); Associated with dyskeratosis congenita.

What condition is associated with TERT p.Arg577Trp (c.1729C>T)?

TERT p.Arg577Trp (c.1729C>T) is associated with dyskeratosis congenita, dyskeratosis congenita, autosomal dominant 2, idiopathic pulmonary fibrosis (ClinVar).

How common is TERT p.Arg577Trp (c.1729C>T) in the general population?

TERT p.Arg577Trp (c.1729C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Dyskeratosis congenita inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TERT p.Arg577Trp (c.1729C>T)?

AlphaMissense predicts likely pathogenic (score 0.6018) — an in-silico prediction, not a clinical call.

TERT p.Arg577Trp

c.1729C>T · rs1207489144 · VCV861105

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6018 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.6018	likely pathogenic
REVEL	0.884	moderately pathogenic-leaning
SaProt	LLR -15.65	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 7.2, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 29 kb · p 2.3e-32 · regional, not allelic
Overall
CADD	29.3	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 0.00223% East Asian · 1/44,888 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000274% 4/1,461,846 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,888
Admixed American	0.00167%	60,026
European (non-Finnish)	0.000169%	590,009

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.Arg577Trp
Coding: c.1729C>T
MANE Select: NM_198253
dbSNP: rs1207489144
Type: single nucleotide variant
Location: chr5:1282469 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.98 · 32 PDB
Residue 577: a β-strand

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

Disease context

dyskeratosis congenita — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyskeratosis congenita, autosomal dominant 2 idiopathic pulmonary fibrosis

For Dyskeratosis congenita (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

TERT p.Arg577= Likely benign ★★ same residue
TERT p.Arg577Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg577trp (accessed [today's date]).

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