# NM_006565.4(CTCF):c.1186dup (p.Arg396fs)

https://sugi.bio/variant/ctcf-p-arg396fs

## Summary

**CTCF p.Arg396fs (c.1186dup)** is classified **Pathogenic** in CTCF (ClinVar, Single submitter, 2 submitters; last evaluated 2019-12-21). Ultra-rare (gnomAD MAF 2.882e-06); Associated with CTCF-related neurodevelopmental disorder.

**At a glance:** Pathogenic · review: Single submitter · rsID rs879255571 · 2 submitters · 1 linked condition · ultra-rare (gnomAD MAF 2.882e-06)

## For patients & families {#patients}

This is a change in the CTCF gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to CTCF-related neurodevelopmental 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Antenatal, Childhood, Infancy, Neonatal |
| Diagnostic panels | CTCF is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of CTCF-related neurodevelopmental disorder** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Cryptorchidism — Frequent (79-30%)
- Abnormality of the dentition — Frequent (79-30%)
- Thin upper lip vermilion — Frequent (79-30%)
- Thin vermilion border — Frequent (79-30%)
- Microcephaly — Frequent (79-30%)
- Strabismus — Frequent (79-30%)
- Long eyelashes — Frequent (79-30%)
- Hypermetropia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017566/index) · [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.Arg396fs |
| Coding change (HGVS c.) | c.1186dup |
| MANE Select transcript | [NM_006565](https://www.ncbi.nlm.nih.gov/nuccore/NM_006565) |
| dbSNP | [rs879255571](https://www.ncbi.nlm.nih.gov/snp/rs879255571/) |
| Variant type | Duplication |
| Location | chr16:67620792-67620793 (GRCh38) |
| ClinVar | [VCV88637](https://www.ncbi.nlm.nih.gov/clinvar/variation/88637/) |

**All HGVS expressions:** `NC_000016.10:g.67620796dup`, `NC_000016.9:g.67654699dup`, `NG_033892.1:g.63390dup`, `NM_001191022.2:c.202dup`, `NM_001363916.2:c.1186dup`, `NM_006565.3:c.1186dupA`, `NM_006565.4:c.1186dup`

## 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 4.925, GERP -0.311, 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 6 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 duplication 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): global (via dbSNP) **0.000288%** — ultra-rare (gnomAD MAF 2.882e-06).

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

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 Single submitter *(criteria provided, single submitter)*, last evaluated 2019-12-21.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2013–2019); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Leipzig Medical Center | Pathogenic | criteria provided, single submitter | research | 2019-12-21 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2013-07-11 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related CTCF variant pages (same residue, condition, or type): [CTCF p.Ala148fs](/variant/ctcf-p-ala148fs), [CTCF p.Asp290fs](/variant/ctcf-p-asp290fs), [CTCF p.Gly111fs](/variant/ctcf-p-gly111fs), [CTCF p.His541fs](/variant/ctcf-p-his541fs), [CTCF p.Tyr25Ter](/variant/ctcf-p-tyr25ter), [CTCF p.Val126fs](/variant/ctcf-p-val126fs), [CTCF p.Val225fs](/variant/ctcf-p-val225fs), [CTCF p.Val50fs](/variant/ctcf-p-val50fs).

### 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 88637). 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.*