Is TERT p.Pro259= (c.777G>T) pathogenic?

TERT p.Pro259= (c.777G>T) is classified Likely benign in TERT (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-16). Very rare (popmax 0.0027%, afr); Associated with dyskeratosis congenita.

What condition is associated with TERT p.Pro259= (c.777G>T)?

TERT p.Pro259= (c.777G>T) is associated with dyskeratosis congenita (ClinVar).

How common is TERT p.Pro259= (c.777G>T) in the general population?

TERT p.Pro259= (c.777G>T) is very rare (popmax 0.0027%, afr) (gnomAD).

How is Dyskeratosis congenita inherited?

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

TERT p.Pro259=

c.777G>T · rs746036694 · VCV1760597

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0027%, afr)

Conditions

dyskeratosis congenita

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.97	GERP -2.6
Overall
CADD	0.843	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0027% African / African-American · 2/74,200 alleles

Filtering AF 0.000447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000252% 4/1,585,246 alleles · very rare exomes 2/1,433,006 · genomes 2/152,240 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0027%	37,100
South Asian	0.00227%	43,988

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.Pro259=
Coding: c.777G>T
MANE Select: NM_198253
dbSNP: rs746036694
Type: single nucleotide variant
Location: chr5:1294109 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.98 · 32 PDB
Residue 259: the 'disordered' region; the 'linker' region

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

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.Pro259Arg Uncertain significance ★ ⚠ same residue
TERT p.Pro259Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TERT p.Pro259Gln Uncertain significance ★ ⚠ same residue
TERT c.2286+1G>A Likely pathogenic ★★ same condition
TERT p.Ala716Val Pathogenic/Likely pathogenic ★★ same condition
TERT p.Arg230Ter Pathogenic ★★ same condition
TERT p.Arg631Gln Pathogenic ★★ same condition
TERT p.Arg631Trp 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-pro259 (accessed [today's date]).

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