Is TERT p.Ala751Val (c.2252C>T) pathogenic?

TERT p.Ala751Val (c.2252C>T) is classified Uncertain significance in TERT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-15). AlphaMissense: likely benign (0.1077); Absent from gnomAD v4.1; Associated with dyskeratosis congenita.

What condition is associated with TERT p.Ala751Val (c.2252C>T)?

TERT p.Ala751Val (c.2252C>T) is associated with dyskeratosis congenita (ClinVar).

How common is TERT p.Ala751Val (c.2252C>T) in the general population?

TERT p.Ala751Val (c.2252C>T) is absent from gnomAD v4.1 (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.Ala751Val (c.2252C>T)?

AlphaMissense predicts likely benign (score 0.1077) — an in-silico prediction, not a clinical call.

TERT p.Ala751Val

c.2252C>T · rs2478267831 · VCV2454089

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1077 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.1077	likely benign
REVEL	0.373	indeterminate
SaProt	LLR -8.27	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP -0.037, phastCons 0.64
Regional constraint	o/e 0.58	unconstrained · MANE · 29 kb · p 2.3e-32 · regional, not allelic
Overall
CADD	20.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TERT
Protein: p.Ala751Val
Coding: c.2252C>T
MANE Select: NM_198253
dbSNP: rs2478267831
Type: single nucleotide variant
Location: chr5:1278675 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.98 · 32 PDB
Residue 751: the reverse transcriptase domain

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.Ala751Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
TERT p.Ala751= Likely benign ★ same residue
TERT p.Ala751Ser 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-ala751val (accessed [today's date]).

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