Is TERT p.Ala751Thr (c.2251G>A) pathogenic?

TERT p.Ala751Thr (c.2251G>A) is classified Conflicting classifications of pathogenicity in TERT (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-02). AlphaMissense: likely benign (0.0784); Very rare (popmax 0.00407%, nfe); Associated with dyskeratosis congenita.

What condition is associated with TERT p.Ala751Thr (c.2251G>A)?

TERT p.Ala751Thr (c.2251G>A) is associated with dyskeratosis congenita, dyskeratosis congenita, autosomal dominant 2, idiopathic pulmonary fibrosis (ClinVar).

How common is TERT p.Ala751Thr (c.2251G>A) in the general population?

TERT p.Ala751Thr (c.2251G>A) is very rare (popmax 0.00407%, 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.Ala751Thr (c.2251G>A)?

AlphaMissense predicts likely benign (score 0.0784) — an in-silico prediction, not a clinical call.

TERT p.Ala751Thr

c.2251G>A · rs772070672 · VCV665424

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0784 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00407%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dyskeratosis congenita

Computational evidence

Protein change
AlphaMissense	0.0784	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -8.22	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 -1.4	GERP -1.7
Regional constraint	o/e 0.58	unconstrained · MANE · 29 kb · p 2.3e-32 · regional, not allelic
Overall
CADD	13.71	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 0.00407% European (non-Finnish) · 48/1,180,050 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00335% 54/1,614,154 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00407%	24,584
South Asian	0.00329%	30,362
Remaining individualsnot grpmax-eligible	0.0032%	31,255
African / African-American	0.00133%	75,058

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.Ala751Thr
Coding: c.2251G>A
MANE Select: NM_198253
dbSNP: rs772070672
Type: single nucleotide variant
Location: chr5:1278676 (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

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.Ala751Ser Uncertain significance ★ ⚠ same residue
TERT p.Ala751Val Uncertain significance ★ ⚠ same residue
TERT p.Ala751= 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
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-ala751thr (accessed [today's date]).

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