# NM_025099.6(CTC1):c.1728G>A (p.Pro576=)

https://sugi.bio/variant/ctc1-p-pro576

## Summary

**CTC1 p.Pro576= (c.1728G>A)** is classified **Conflicting classifications of pathogenicity** in CTC1 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-02-02). Rare (popmax 0.226%, nfe); Associated with dyskeratosis congenita.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs78320653 · 11 submitters · 2 linked conditions · rare (popmax 0.226%, nfe)

## For patients & families {#patients}

This is a change in the CTC1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 11 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.Pro576= |
| Coding change (HGVS c.) | c.1728G>A |
| MANE Select transcript | [NM_025099](https://www.ncbi.nlm.nih.gov/nuccore/NM_025099) |
| dbSNP | [rs78320653](https://www.ncbi.nlm.nih.gov/snp/rs78320653/) |
| Variant type | single nucleotide variant |
| Location | chr17:8234545-8234545 (GRCh38) |
| ClinVar | [VCV326079](https://www.ncbi.nlm.nih.gov/clinvar/variation/326079/) |

**All HGVS expressions:** `LRG_1124:g.18551G>A`, `LRG_1124t1:c.1728G>A`, `NC_000017.10:g.8137863C>T`, `NC_000017.11:g.8234545C>T`, `NG_032148.2:g.18551G>A`, `NM_025099.6:c.1728G>A`, `NR_046431.2:n.1643G>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 -2.958, GERP -3.45 — fast-evolving / accelerated position
- CADD: **PHRED 8.28**. 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 **0.226%** (nfe) · FAF95 0.219% · FAF99 0.216% · 2,625/1,159,642 in the highest group · 2,934/1,574,920 alleles overall — rare (popmax 0.226%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.226% | 442 |
| Admixed American | 0.18% | 554 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.18% | 555 |
| Remaining individuals (not grpmax-eligible) | 0.156% | 643 |
| Finnish (not grpmax-eligible) | 0.0438% | 2,281 |
| African / African-American | 0.0269% | 3,715 |
| South Asian | 0.0208% | 4,797 |
| East Asian | 0.00233% | 42,950 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (7 Likely benign, 2 Uncertain significance, 1 Benign).

**Submission history:** 13 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2016-05-05 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-23 |
| Genome-Nilou Lab | Likely benign | criteria provided, single submitter | clinical testing | 2021-07-15 |
| Sema4, Sema4 | Uncertain significance | criteria provided, single submitter | curation | 2022-02-24 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-04-18 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-07-14 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-22 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-01 |

## Associated conditions {#conditions}

[dyskeratosis congenita](https://sugi.bio/atlas/disease/dyskeratosis-congenita/), [cerebroretinal microangiopathy with calcifications and cysts 1](https://sugi.bio/atlas/disease/cerebroretinal-microangiopathy-with-calcifications-and-cysts-1/).

**Reported phenotype names (ClinVar):** Dyskeratosis congenita, not specified, not provided, Cerebroretinal microangiopathy with calcifications and cysts 1, CTC1-related disorder, Acute myeloid leukemia, Gastric cancer, Malignant tumor of esophagus, none provided, CTC1-related condition.

## Similar variants {#similar}

Related CTC1 variant pages (same residue, condition, or type): [CTC1 p.Pro576Leu](/variant/ctc1-p-pro576leu), [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), [CTC1 c.3221+1G>A](/variant/ctc1-c-3221-plus-1g-a), [CTC1 p.Ala227Val](/variant/ctc1-p-ala227val), [CTC1 p.Arg108Ter](/variant/ctc1-p-arg108ter).

### 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 326079). 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.*