# NM_005652.5(TERF2):c.1155C>T (p.Asp385=)

https://sugi.bio/variant/terf2-p-asp385

## Summary

**TERF2 p.Asp385= (c.1155C>T)** is classified **Likely benign** in TERF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-12). Very rare (popmax 0.005%, amr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the TERF2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TERF2](https://sugi.bio/atlas/gene/TERF2/) |
| Protein change (HGVS p.) | p.Asp385= |
| Coding change (HGVS c.) | c.1155C>T |
| MANE Select transcript | [NM_005652](https://www.ncbi.nlm.nih.gov/nuccore/NM_005652) |
| Variant type | single nucleotide variant |
| Location | chr16:69366992-69366992 (GRCh38) |
| ClinVar | [VCV4930661](https://www.ncbi.nlm.nih.gov/clinvar/variation/4930661/) |

**All HGVS expressions:** `NC_000016.10:g.69366992G>A`, `NC_000016.9:g.69400895G>A`, `NM_005652.5:c.1155C>T`

## 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 2.936, GERP -0.812, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.6**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.31 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.005%** (amr) · FAF95 0.00231% · FAF99 0.00202% · 3/60,004 in the highest group · 46/1,614,080 alleles overall — very rare (popmax 0.005%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.005% | 20,001 |
| South Asian | 0.00439% | 22,773 |
| European (non-Finnish) | 0.00314% | 31,893 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,024 |
| African / African-American | 0.00133% | 74,926 |

*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}

**TERF2** population constraint: LOEUF 0.444, pLI 0.99897, missense-Z 1.6747. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **385** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 69.36, 41% of residues very-high.

**18 experimental structure(s)** (PDB): [1H6P](https://www.rcsb.org/structure/1H6P), [1VF9](https://www.rcsb.org/structure/1VF9), [1VFC](https://www.rcsb.org/structure/1VFC), [1W0U](https://www.rcsb.org/structure/1W0U), [1XG1](https://www.rcsb.org/structure/1XG1), [3BU8](https://www.rcsb.org/structure/3BU8).

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

*Describes the biological roles of TERF2 (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:** TERF2's established molecular role includes double-stranded telomeric DNA binding. p.Asp385= falls in the disordered region.


### Pathways affected {#pathways}

TERF2 participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | curated |
| [Inhibition of DNA recombination at telomere](https://reactome.org/content/detail/R-HSA-9670095) | curated |
| [Packaging Of Telomere Ends](https://reactome.org/content/detail/R-HSA-171306) | curated |
| [Polymerase switching on the C-strand of the telomere](https://reactome.org/content/detail/R-HSA-174411) | curated |
| [Processive synthesis on the C-strand of the telomere](https://reactome.org/content/detail/R-HSA-174414) | curated |
| [Removal of the Flap Intermediate from the C-strand](https://reactome.org/content/detail/R-HSA-174437) | curated |
| [Telomere C-strand (Lagging Strand) Synthesis](https://reactome.org/content/detail/R-HSA-174417) | curated |
| [Telomere C-strand synthesis initiation](https://reactome.org/content/detail/R-HSA-174430) | curated |
| [Telomere Extension By Telomerase](https://reactome.org/content/detail/R-HSA-171319) | curated |
| [Cleavage of the damaged purine](https://reactome.org/content/detail/R-HSA-110331) | electronic |
| [Cleavage of the damaged pyrimidine ](https://reactome.org/content/detail/R-HSA-110329) | electronic |
| [Meiotic synapsis](https://reactome.org/content/detail/R-HSA-1221632) | electronic |
| [Recognition and association of DNA glycosylase with site containing an affected purine](https://reactome.org/content/detail/R-HSA-110330) | electronic |
| [Recognition and association of DNA glycosylase with site containing an affected pyrimidine](https://reactome.org/content/detail/R-HSA-110328) | electronic |

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

**Molecular function:** double-stranded telomeric DNA binding, enzyme binding, telomeric repeat DNA binding, protein homodimerization activity, protein-containing complex binding, G-rich strand telomeric DNA binding.

**Biological process:** telomere maintenance, telomere capping, telomeric loop formation, protection from non-homologous end joining at telomere, regulation of telomere maintenance, negative regulation of telomere maintenance.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-12.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-12 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related TERF2 variant pages (same residue, condition, or type): [TERF2 c.1341-42T>C](/variant/terf2-c-1341-minus-42t-c), [TERF2 c.1426+95C>T](/variant/terf2-c-1426-plus-95c-t), [TERF2 c.380-5C>T](/variant/terf2-c-380-minus-5c-t), [TERF2 c.840+145C>T](/variant/terf2-c-840-plus-145c-t), [TERF2 c.947+27G>A](/variant/terf2-c-947-plus-27g-a), [TERF2 c.*142G>A](/variant/terf2-c-star-142g-a), [TERF2 c.*159C>T](/variant/terf2-c-star-159c-t), [TERF2 c.*220A>G](/variant/terf2-c-star-220a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4930661). 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.*