# NM_006565.4(CTCF):c.778_781del (p.Lys260fs)

https://sugi.bio/variant/ctcf-p-lys260fs

## Summary

**CTCF p.Lys260fs (c.778_781del)** is classified **Pathogenic** in CTCF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2020-07-13). No gnomAD frequency available for this variant; Associated with CTCF-related disorder.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs2052063931 · 4 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CTCF gene that is considered disease-causing, submitted by 4 submitters, and is linked to CTCF-related disorder.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CTCF](https://sugi.bio/atlas/gene/CTCF/) |
| Protein change (HGVS p.) | p.Lys260fs |
| Coding change (HGVS c.) | c.778_781del |
| MANE Select transcript | [NM_006565](https://www.ncbi.nlm.nih.gov/nuccore/NM_006565) |
| dbSNP | [rs2052063931](https://www.ncbi.nlm.nih.gov/snp/rs2052063931/) |
| Variant type | Microsatellite |
| Location | chr16:67611606-67611609 (GRCh38) |
| ClinVar | [VCV984936](https://www.ncbi.nlm.nih.gov/clinvar/variation/984936/) |

**All HGVS expressions:** `NC_000016.10:g.67611606AAAG[1]`, `NC_000016.9:g.67645509AAAG[1]`, `NG_033892.1:g.54200AAAG[1]`, `NM_001191022.2:c.-32-5135_-32-5132del`, `NM_001363916.2:c.774_777AAAG[1]`, `NM_006565.3:c.778_781delAAAG`, `NM_006565.4:c.778_781del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.212, GERP 2.78, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.205, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 12**, 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CTCF** population constraint: LOEUF 0.205, pLI 1, missense-Z 4.8464; ClinGen dosage — haploinsufficiency 3, 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):

- **syndromic intellectual disability** — Definitive (AD)

## Protein context {#protein}

Residue **260** lies in a UniProt-annotated variant site (found in an endometrial carcinoma sample; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 59.45, 1% of residues very-high.

**21 experimental structure(s)** (PDB): [1X6H](https://www.rcsb.org/structure/1X6H), [2CT1](https://www.rcsb.org/structure/2CT1), [5K5H](https://www.rcsb.org/structure/5K5H), [5K5I](https://www.rcsb.org/structure/5K5I), [5K5J](https://www.rcsb.org/structure/5K5J), [5K5L](https://www.rcsb.org/structure/5K5L) — incl. mutant structure 8SST.

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

*Describes the biological roles of CTCF (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:** CTCF's established molecular role includes transcription cis-regulatory region binding.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CHD6, CHD7, CHD8, CHD9 subfamily](https://reactome.org/content/detail/R-HSA-9943962) | curated |
| [Activation of anterior HOX genes in hindbrain development during early embryogenesis](https://reactome.org/content/detail/R-HSA-5617472) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, transcription coregulator binding, DNA-binding transcription repressor activity, RNA polymerase II-specific, DNA-binding transcription factor activity, chromatin insulator sequence binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, negative regulation of cell population proliferation, positive regulation of gene expression, epigenetic regulation of gene expression, negative regulation of DNA-templated transcription, positive regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2020-07-13.

**Submitter consensus:** conflicting (3 Pathogenic, 1 not provided).

**Submission history:** 4 submissions (2020); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Pathogenic | criteria provided, single submitter | clinical testing | 2020-02-19 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2020-06-11 |
| GenomeConnect - Brain Gene Registry | not provided | no classification provided | phenotyping only |  |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2020-07-13 |

## Associated conditions {#conditions}

[CTCF-related disorder](https://sugi.bio/atlas/disease/ctcf-related-disorder/), [CTCF-related neurodevelopmental disorder](https://sugi.bio/atlas/disease/ctcf-related-neurodevelopmental-disorder/).

**Reported phenotype names (ClinVar):** CTCF-related disorder, CTCF-related neurodevelopmental disorder, CTCF-related condition, INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 21, Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome.

## Similar variants {#similar}

Related CTCF variant pages (same residue, condition, or type): [CTCF p.Cys268_Glu269delinsTer](/variant/ctcf-p-cys268-glu269delinster), [CTCF c.782-1G>A](/variant/ctcf-c-782-minus-1g-a), [CTCF c.782-1G>C](/variant/ctcf-c-782-minus-1g-c), [CTCF c.782-2A>G](/variant/ctcf-c-782-minus-2a-g), [CTCF c.782-2A>T](/variant/ctcf-c-782-minus-2a-t), [CTCF p.Arg283His](/variant/ctcf-p-arg283his), [CTCF p.Arg342Cys](/variant/ctcf-p-arg342cys), [CTCF p.Arg342His](/variant/ctcf-p-arg342his).

### 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 984936). 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.*