# NM_025099.6(CTC1):c.1966_1967del (p.Arg656fs)

https://sugi.bio/variant/ctc1-p-arg656fs

## Summary

**CTC1 p.Arg656fs (c.1966_1967del)** is classified **Pathogenic** in CTC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). Very rare (popmax 0.00329%, sas); Associated with dyskeratosis congenita.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00329%, sas)

## For patients & families {#patients}

This is a change in the CTC1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to dyskeratosis congenita.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 19 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CTC1 is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Dyskeratosis congenita** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypermelanotic macule — Very frequent (99-80%)
- Abnormal fingernail morphology — Very frequent (99-80%)
- Thrombocytopenia — Very frequent (99-80%)
- Abnormality of neutrophils — Very frequent (99-80%)
- Anemia — Very frequent (99-80%)
- Oral leukoplakia — Very frequent (99-80%)
- Abnormal blistering of the skin — Very frequent (99-80%)
- Nail dystrophy — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010905/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CTC1](https://sugi.bio/atlas/gene/CTC1/) |
| Protein change (HGVS p.) | p.Arg656fs |
| Coding change (HGVS c.) | c.1966_1967del |
| MANE Select transcript | [NM_025099](https://www.ncbi.nlm.nih.gov/nuccore/NM_025099) |
| Variant type | Microsatellite |
| Location | chr17:8232454-8232455 (GRCh38) |
| ClinVar | [VCV4782291](https://www.ncbi.nlm.nih.gov/clinvar/variation/4782291/) |

**All HGVS expressions:** `LRG_1124:g.20637AG[2]`, `LRG_1124t1:c.1966_1967del`, `NC_000017.10:g.8135772CT[2]`, `NC_000017.11:g.8232454CT[2]`, `NG_032148.2:g.20637AG[2]`, `NM_001411067.1:c.1966_1967del`, `NM_025099.6:c.1966_1967del`, `NR_046431.2:n.1877AG[2]`

## 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 0.609, GERP 1.73, phastCons 0.112 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.776, pLI 4.0781e-18. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 12 of 23**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00329%** (sas) · FAF95 0.000875% · FAF99 0.000443% · 3/91,084 in the highest group · 4/1,461,838 alleles overall — very rare (popmax 0.00329%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00329% | 30,361 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,510 |

*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}

**CTC1** population constraint: LOEUF 0.776, pLI 4.0781e-18, missense-Z 1.0969; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **cerebroretinal microangiopathy with calcifications and cysts 1** — Definitive (AR)

## Protein context {#protein}

Residue **656** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 78.01, 20% of residues very-high.

**7 experimental structure(s)** (PDB): [5W2L](https://www.rcsb.org/structure/5W2L), [6W6W](https://www.rcsb.org/structure/6W6W), [7U5C](https://www.rcsb.org/structure/7U5C), [8D0B](https://www.rcsb.org/structure/8D0B), [8D0K](https://www.rcsb.org/structure/8D0K), [8SOJ](https://www.rcsb.org/structure/8SOJ).

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

*Describes the biological roles of CTC1 (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:** CTC1's established molecular role includes telomeric repeat DNA binding.


### Pathways affected {#pathways}

CTC1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Polymerase switching on the C-strand of the telomere](https://reactome.org/content/detail/R-HSA-174411) | curated |
| [Telomere C-strand synthesis initiation](https://reactome.org/content/detail/R-HSA-174430) | curated |

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

**Molecular function:** telomeric repeat DNA binding, G-rich strand telomeric DNA binding.

**Biological process:** telomere maintenance, negative regulation of telomere maintenance via telomerase.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-07.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-07 |

## Associated conditions {#conditions}

[dyskeratosis congenita](https://sugi.bio/atlas/disease/dyskeratosis-congenita/).

**Reported phenotype names (ClinVar):** Dyskeratosis congenita.

## Similar variants {#similar}

Related CTC1 variant pages (same residue, condition, or type): [CTC1 p.Cys985del](/variant/ctc1-p-cys985del), [CTC1 p.Ser357fs](/variant/ctc1-p-ser357fs), [CTC1 p.Glu558del](/variant/ctc1-p-glu558del), [CTC1 p.Ala605fs](/variant/ctc1-p-ala605fs), [CTC1 p.Arg136_Asp137insTer](/variant/ctc1-p-arg136-asp137inster), [CTC1 p.Leu597fs](/variant/ctc1-p-leu597fs), [CTC1 c.1819-7_1819-5del](/variant/ctc1-c-1819-minus-7-1819-minus-5del), [CTC1 c.1439+7_1439+9del](/variant/ctc1-c-1439-plus-7-1439-plus-9del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 4782291). 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.*