# NM_025099.6(CTC1):c.435+3=

https://sugi.bio/variant/ctc1-c-435-plus-3

## Summary

**CTC1 c.435+3=** is classified **Benign** in CTC1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Absent from gnomAD v4.1; Associated with cerebroretinal microangiopathy with calcifications and cysts 1.

**At a glance:** Benign · review: Multiple submitters · rsID rs6503093 · 9 submitters · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CTC1 gene that is classified as benign — not considered disease-causing, submitted by 9 submitters, and is linked to cerebroretinal microangiopathy with calcifications and cysts 1.

*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 recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | <1 / 1 000 000 (Europe) |
| Diagnostic panels | CTC1 is a diagnostic-grade gene on 11 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018441/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CTC1](https://sugi.bio/atlas/gene/CTC1/) |
| Coding change (HGVS c.) | c.435+3= |
| MANE Select transcript | [NM_025099](https://www.ncbi.nlm.nih.gov/nuccore/NM_025099) |
| dbSNP | [rs6503093](https://www.ncbi.nlm.nih.gov/snp/rs6503093/) |
| Variant type | single nucleotide variant |
| Location | chr17:8238389-8238389 (GRCh38) |
| ClinVar | [VCV261822](https://www.ncbi.nlm.nih.gov/clinvar/variation/261822/) |

**All HGVS expressions:** `LRG_1124:g.14707=`, `LRG_1124t1:c.435+3=`, `NC_000017.10:g.8141707T>C`, `NC_000017.11:g.8238389=`, `NG_032148.2:g.14707=`, `NM_025099.6:c.435+3=`

## 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 0.085, GERP -5.21, phastCons 0.924 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Splice region: **donor splice region (+3, within the first 6 intronic nt)** — inside the zone ClinGen GN167 excludes from BP7, so this variant must not be called benign merely for being synonymous or intronic.
- Non-coding constraint (Gnocchi): **Z 3.10**, o/e 0.77 (1 kb window 8,238,000–8,239,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.53 donor loss), 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (9/9 Benign).

**Submission history:** 9 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-07-28 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-28 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-11-28 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cerebroretinal microangiopathy with calcifications and cysts 1, not specified, Dyskeratosis congenita, not provided, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related CTC1 variant pages (same residue, condition, or type): [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), [CTC1 p.Arg1195Ter](/variant/ctc1-p-arg1195ter).

### 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 261822). 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.*