# NM_025099.6(CTC1):c.1681C>A (p.Arg561Ser)

https://sugi.bio/variant/ctc1-p-arg561ser

## Summary

**CTC1 p.Arg561Ser (c.1681C>A)** is classified **Uncertain significance** in CTC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-20). AlphaMissense: likely benign (0.1494); Very rare (popmax 0.00842%, amr); Associated with dyskeratosis congenita.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs202212634 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00842%, amr)

## For patients & families {#patients}

This is a change in the CTC1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, 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.Arg561Ser |
| Coding change (HGVS c.) | c.1681C>A |
| MANE Select transcript | [NM_025099](https://www.ncbi.nlm.nih.gov/nuccore/NM_025099) |
| dbSNP | [rs202212634](https://www.ncbi.nlm.nih.gov/snp/rs202212634/) |
| Variant type | single nucleotide variant |
| Location | chr17:8234592-8234592 (GRCh38) |
| ClinVar | [VCV529174](https://www.ncbi.nlm.nih.gov/clinvar/variation/529174/) |

**All HGVS expressions:** `LRG_1124:g.18504C>A`, `LRG_1124t1:c.1681C>A`, `NC_000017.10:g.8137910G>T`, `NC_000017.11:g.8234592G>T`, `NG_032148.2:g.18504C>A`, `NM_025099.6:c.1681C>A`, `NR_046431.2:n.1596C>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1494)
- REVEL 0.164 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.212 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -1.377, GERP -3.45 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.654**. 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.*
- Regional missense constraint: **o/e 0.96** across the covering region of the MANE Select transcript (8,228,183–8,248,036), spanning 19,853 bp. Chi-square p 0.088. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.73 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 **0.00842%** (amr) · FAF95 0.00326% · FAF99 0.00209% · 5/59,352 in the highest group · 7/1,458,372 alleles overall — very rare (popmax 0.00842%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00842% | 11,870 |
| European (non-Finnish) | 0.00017% | 589,254 |

*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}


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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-20.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-20 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-26 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Dyskeratosis congenita, Inborn genetic diseases.

## Similar variants {#similar}

Related CTC1 variant pages (same residue, condition, or type): [CTC1 p.Arg561His](/variant/ctc1-p-arg561his), [CTC1 p.Arg561Pro](/variant/ctc1-p-arg561pro), [CTC1 p.Arg561=](/variant/ctc1-p-arg561), [CTC1 p.Arg561Cys](/variant/ctc1-p-arg561cys), [CTC1 c.1617+5G>T](/variant/ctc1-c-1617-plus-5g-t), [CTC1 c.1818+1G>A](/variant/ctc1-c-1818-plus-1g-a), [CTC1 c.2386-1G>A](/variant/ctc1-c-2386-minus-1g-a), [CTC1 c.2758+1G>T](/variant/ctc1-c-2758-plus-1g-t).

### 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 529174). 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.*