Is TERT p.Arg108Ser (c.322C>A) pathogenic?

TERT p.Arg108Ser (c.322C>A) is classified Uncertain significance in TERT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-22). AlphaMissense: likely benign (0.1984); Very rare (popmax 8.53e-05%, nfe); Associated with dyskeratosis congenita.

What condition is associated with TERT p.Arg108Ser (c.322C>A)?

TERT p.Arg108Ser (c.322C>A) is associated with dyskeratosis congenita, dyskeratosis congenita, autosomal dominant 2, idiopathic pulmonary fibrosis (ClinVar).

How common is TERT p.Arg108Ser (c.322C>A) in the general population?

TERT p.Arg108Ser (c.322C>A) is very rare (popmax 8.53e-05%, nfe) (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.Arg108Ser (c.322C>A)?

AlphaMissense predicts likely benign (score 0.1984) — an in-silico prediction, not a clinical call.

TERT p.Arg108Ser

c.322C>A · rs1478218565 · VCV573481

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.1984	likely benign
REVEL	0.274	benign-leaning
SaProt	LLR -6.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 4.1, phastCons 0.058
Regional constraint	o/e 0.45	unconstrained · MANE · 213 bp · p 1.3e-08 · regional, not allelic
Overall
CADD	8.124	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.53e-05% European (non-Finnish) · 1/1,172,782 alleles

Overall 6.99e-05% 1/1,431,410 alleles · very rare

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.Arg108Ser
Coding: c.322C>A
MANE Select: NM_198253
dbSNP: rs1478218565
Type: single nucleotide variant
Location: chr5:1294564 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.98 · 32 PDB
Residue 108: the 'rna-interacting domain 1' region; the 'gq motif' 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

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.Arg108Cys Uncertain significance ★ ⚠ same residue
TERT p.Arg108Gly Uncertain significance ★ ⚠ same residue
TERT p.Arg108Leu Uncertain significance ★ ⚠ same residue
TERT p.Arg108= 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

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-arg108ser (accessed [today's date]).

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