Is TERT p.Val170Met (c.508G>A) pathogenic?

TERT p.Val170Met (c.508G>A) is classified Conflicting classifications of pathogenicity in TERT (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-07-08). AlphaMissense: likely pathogenic (0.6491); Very rare (popmax 0.00316%, nfe); Associated with dyskeratosis congenita, autosomal dominant 2.

What condition is associated with TERT p.Val170Met (c.508G>A)?

TERT p.Val170Met (c.508G>A) is associated with dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 1, pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 (ClinVar).

How common is TERT p.Val170Met (c.508G>A) in the general population?

TERT p.Val170Met (c.508G>A) is very rare (popmax 0.00316%, 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.Val170Met (c.508G>A)?

AlphaMissense predicts likely pathogenic (score 0.6491) — an in-silico prediction, not a clinical call.

TERT p.Val170Met

c.508G>A · rs387907248 · VCV36947

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6491 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00316%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyskeratosis congenita, autosomal dominant 2

Computational evidence

Protein change
AlphaMissense	0.6491	likely pathogenic
REVEL	0.686	pathogenic-leaning
SaProt	LLR -8.74	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP 7.4, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 213 bp · p 1.3e-08 · regional, not allelic
Overall
CADD	24.0	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 0.00316% European (non-Finnish) · 37/1,170,584 alleles

Filtering AF 0.00233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00204%

Overall 0.00266% 38/1,426,780 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00316%	31,637
African / African-American	0.00134%	74,656

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.Val170Met
Coding: c.508G>A
MANE Select: NM_198253
dbSNP: rs387907248
Type: single nucleotide variant
Location: chr5:1294378 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.98 · 32 PDB
Residue 170: the 'rna-interacting domain 1' region; the 'gq motif' region; a UniProt-annotated variant site (in pfbmft1; the mutant protein is demonstrated to cause decreased telomerase activity)

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

Disease context

dyskeratosis congenita, autosomal dominant 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyskeratosis congenita, autosomal dominant 1 pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 melanoma, cutaneous malignant, susceptibility to, 9 dyskeratosis congenita aplastic anemia acute myeloid leukemia interstitial lung disease 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.Val170Leu Uncertain significance ★★ ⚠ same residue
TERT p.Val170= Likely benign ★ same residue
TERT p.Val170_Gln177del 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-val170met (accessed [today's date]).

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