# NM_025099.6(CTC1):c.1070_1074del (p.Ser357fs)

https://sugi.bio/variant/ctc1-p-ser357fs

## Summary

**CTC1 p.Ser357fs (c.1070_1074del)** is classified **Pathogenic/Likely pathogenic** in CTC1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-27). Ultra-rare (popmax 0.0165%, sas); Associated with cerebroretinal microangiopathy with calcifications and cysts 1.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs773120259 · 4 submitters · 2 linked conditions · ultra-rare (popmax 0.0165%, sas)

## For patients & families {#patients}

This is a change in the CTC1 gene that is considered likely disease-causing, submitted by 4 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/) |
| Protein change (HGVS p.) | p.Ser357fs |
| Coding change (HGVS c.) | c.1070_1074del |
| MANE Select transcript | [NM_025099](https://www.ncbi.nlm.nih.gov/nuccore/NM_025099) |
| dbSNP | [rs773120259](https://www.ncbi.nlm.nih.gov/snp/rs773120259/) |
| Variant type | Microsatellite |
| Location | chr17:8236061-8236065 (GRCh38) |
| ClinVar | [VCV862044](https://www.ncbi.nlm.nih.gov/clinvar/variation/862044/) |

**All HGVS expressions:** `LRG_1124:g.17026CCTAT[1]`, `LRG_1124t1:c.1070_1074del`, `NC_000017.10:g.8139380TAGGA[1]`, `NC_000017.11:g.8236062TAGGA[1]`, `NG_032148.2:g.17026CCTAT[1]`, `NM_025099.6:c.1070_1074del`, `NM_025099.6:c.1070_1074delCCTAT`, `NR_046431.2:n.980CCTAT[1]`

## 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 0.32, GERP -4.81 — 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 6 of 23**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 26.6**. 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: **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 **0.0165%** (sas) · FAF95 0.0101% · FAF99 0.00811% · 15/91,036 in the highest group · 52/1,611,134 alleles overall — ultra-rare (popmax 0.0165%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0165% | 6,069 |
| Remaining individuals (not grpmax-eligible) | 0.00481% | 20,793 |
| African / African-American | 0.00401% | 24,953 |
| European (non-Finnish) | 0.00263% | 37,990 |

*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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-27.

**Submitter consensus:** conflicting (2 Likely pathogenic, 2 Pathogenic).

**Submission history:** 4 submissions (2021–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-04-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-22 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-27 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-09-18 |

## 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, Dyskeratosis congenita, CTC1-related disorder, CTC1-related condition.

## Similar variants {#similar}

Related CTC1 variant pages (same residue, condition, or type): [CTC1 p.Asp44fs](/variant/ctc1-p-asp44fs), [CTC1 p.Cys985del](/variant/ctc1-p-cys985del), [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.Arg656fs](/variant/ctc1-p-arg656fs), [CTC1 p.Leu597fs](/variant/ctc1-p-leu597fs), [CTC1 c.1819-7_1819-5del](/variant/ctc1-c-1819-minus-7-1819-minus-5del).

### 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 862044). 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.*