# NM_198253.3(TERT):c.3324G>A (p.Pro1108=)

https://sugi.bio/variant/tert-p-pro1108

## Summary

**TERT p.Pro1108= (c.3324G>A)** is classified **Benign/Likely benign** in TERT (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-03). Low-frequency (popmax 2.57%, nfe); Associated with aplastic anemia.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs35033501 · 14 submitters · 5 linked conditions · low-frequency (popmax 2.57%, nfe)

## For patients & families {#patients}

This is a change in the TERT gene that is classified as benign/likely benign — not considered disease-causing, submitted by 14 submitters, and is linked to aplastic anemia.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 232 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0020234/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TERT](https://sugi.bio/atlas/gene/TERT/) |
| Protein change (HGVS p.) | p.Pro1108= |
| Coding change (HGVS c.) | c.3324G>A |
| MANE Select transcript | [NM_198253](https://www.ncbi.nlm.nih.gov/nuccore/NM_198253) |
| dbSNP | [rs35033501](https://www.ncbi.nlm.nih.gov/snp/rs35033501/) |
| Variant type | single nucleotide variant |
| Location | chr5:1253803-1253803 (GRCh38) |
| ClinVar | [VCV165375](https://www.ncbi.nlm.nih.gov/clinvar/variation/165375/) |

**All HGVS expressions:** `LRG_343:g.46245G>A`, `LRG_343t1:c.3324G>A`, `NC_000005.10:g.1253803C>T`, `NC_000005.9:g.1253918C>T`, `NG_009265.1:g.46245G>A`, `NM_001193376.3:c.3135G>A`, `NM_198253.3:c.3324G>A`, `NR_149162.3:n.3032G>A`, `NR_149163.3:n.2996G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -15.955, GERP -2.16 — fast-evolving / accelerated position
- CADD: **PHRED 0.085**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **2.57%** (nfe) · FAF95 2.55% · FAF99 2.54% · 30,332/1,179,498 in the highest group · 35,812/1,611,298 alleles overall — low-frequency (popmax 2.57%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 5.49% | 18 |
| Amish (not grpmax-eligible) | 5.48% | 18 |
| European (non-Finnish) (grpmax) | 2.57% | 39 |
| Remaining individuals (not grpmax-eligible) | 1.73% | 58 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.483% | 207 |
| Admixed American | 0.446% | 224 |
| African / African-American | 0.334% | 299 |
| South Asian | 0.235% | 426 |
| Middle Eastern | 0.231% | 433 |
| East Asian | 0.0134% | 7,471 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**TERT** population constraint: LOEUF 0.593, pLI 0.0019285, missense-Z 3.0616; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **dyskeratosis congenita, autosomal dominant 2** — Definitive (SD)

## Protein context {#protein}

Residue **1108** lies in the 'cte' region.

AlphaFold model confidence (whole protein): pLDDT 80.98, 60% of residues very-high.

**32 experimental structure(s)** (PDB): [2BCK](https://www.rcsb.org/structure/2BCK), [4B18](https://www.rcsb.org/structure/4B18), [4MNQ](https://www.rcsb.org/structure/4MNQ), [5MEN](https://www.rcsb.org/structure/5MEN), [5MEO](https://www.rcsb.org/structure/5MEO), [5MEP](https://www.rcsb.org/structure/5MEP).

## What this gene does {#gene-function}

*Describes the biological roles of TERT (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** TERT's established molecular role includes tRNA binding. p.Pro1108= falls in the cte region.


### Pathways affected {#pathways}

TERT participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of the beta-catenin:TCF transactivating complex](https://reactome.org/content/detail/R-HSA-201722) | curated |
| [Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence](https://reactome.org/content/detail/R-HSA-9825895) | curated |
| [Telomere Extension By Telomerase](https://reactome.org/content/detail/R-HSA-171319) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** tRNA binding, transcription coactivator binding, DNA binding, telomerase activity, RNA binding, RNA-directed DNA polymerase activity.

**Biological process:** RNA-templated transcription, RNA-templated DNA biosynthetic process, protein import into nucleus, telomere maintenance via telomerase, mitochondrion organization, DNA strand elongation.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** conflicting (15 Benign, 1 Likely benign).

**Submission history:** 16 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2016-04-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2013-02-21 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2018-10-09 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-07-21 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2025-10-01 |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[aplastic anemia](https://sugi.bio/atlas/disease/aplastic-anemia/), [dyskeratosis congenita, autosomal dominant 2](https://sugi.bio/atlas/disease/dyskeratosis-congenita-autosomal-dominant-2/), [pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1](https://sugi.bio/atlas/disease/pulmonary-fibrosis-and-or-bone-marrow-failure-telomere-related-1/), [dyskeratosis congenita](https://sugi.bio/atlas/disease/dyskeratosis-congenita/), [idiopathic pulmonary fibrosis](https://sugi.bio/atlas/disease/idiopathic-pulmonary-fibrosis/).

**Reported phenotype names (ClinVar):** Aplastic anemia, not specified, Dyskeratosis congenita, autosomal dominant 2, Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1, not provided, Idiopathic Pulmonary Fibrosis, Dyskeratosis congenita, AllHighlyPenetrant, Idiopathic fibrosing alveolitis, chronic form, idiopathic fibrosing alveolitis.

## Similar variants {#similar}

Related TERT variant pages (same residue, condition, or type): [TERT p.Pro1108Arg](/variant/tert-p-pro1108arg), [TERT p.Pro1108Ser](/variant/tert-p-pro1108ser), [TERT p.Pro1108Gln](/variant/tert-p-pro1108gln), [TERT p.Pro1108Leu](/variant/tert-p-pro1108leu), [TERT c.2130+1G>A](/variant/tert-c-2130-plus-1g-a), [TERT c.2130+2T>G](/variant/tert-c-2130-plus-2t-g), [TERT c.2131-2A>G](/variant/tert-c-2131-minus-2a-g), [TERT c.2286+1G>A](/variant/tert-c-2286-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 165375). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*