Is TERT p.His296Pro (c.887A>C) pathogenic?

TERT p.His296Pro (c.887A>C) is classified Conflicting classifications of pathogenicity in TERT (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-09-30). AlphaMissense: likely benign (0.064); Ultra-rare (popmax 0.0254%, nfe); Associated with aplastic anemia.

What condition is associated with TERT p.His296Pro (c.887A>C)?

TERT p.His296Pro (c.887A>C) is associated with aplastic anemia, hepatocellular carcinoma, dyskeratosis congenita, autosomal dominant 1 (ClinVar).

How common is TERT p.His296Pro (c.887A>C) in the general population?

TERT p.His296Pro (c.887A>C) is ultra-rare (popmax 0.0254%, nfe) (gnomAD).

What do computational predictors say about TERT p.His296Pro (c.887A>C)?

AlphaMissense predicts likely benign (score 0.064) — an in-silico prediction, not a clinical call.

TERT p.His296Pro

c.887A>C · rs778187343 · VCV268080

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.064 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

aplastic anemia

Computational evidence

Protein change
AlphaMissense	0.064	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -4.46	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 -2.6	GERP -7.1
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.082 · regional, not allelic
Overall
CADD	1.758	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 0.0254% European (non-Finnish) · 296/1,164,360 alleles

Filtering AF 0.023% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.022%

Overall 0.0191% 301/1,575,612 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0254%	3,934
Remaining individualsnot grpmax-eligible	0.00655%	15,271
Admixed American	0.00181%	55,370

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.His296Pro
Coding: c.887A>C
MANE Select: NM_198253
dbSNP: rs778187343
Type: single nucleotide variant
Location: chr5:1293999 (GRCh38)
Gene constraint: LOEUF 0.593 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 80.98 · 32 PDB
Residue 296: the 'disordered' region; the 'linker' region

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

Disease context

aplastic anemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hepatocellular carcinoma dyskeratosis congenita, autosomal dominant 1 dyskeratosis congenita, autosomal dominant 2 pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1 melanoma, cutaneous malignant, susceptibility to, 9 dyskeratosis congenita acute myeloid leukemia interstitial lung disease 2 idiopathic pulmonary fibrosis

Similar variants

TERT p.His296Tyr 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
TERT p.Ala1009Val Likely pathogenic ★★ same condition
TERT p.Ala716Thr 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-his296pro (accessed [today's date]).

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