# NM_006565.4(CTCF):c.1133C>T (p.Pro378Leu)

https://sugi.bio/variant/ctcf-p-pro378leu

## Summary

**CTCF p.Pro378Leu (c.1133C>T)** is classified **Pathogenic/Likely pathogenic** in CTCF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-20). AlphaMissense: likely pathogenic (0.9987); Very rare (popmax 0.000256%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2142847512 · 4 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.000256%, nfe)

## For patients & families {#patients}

This is a change in the CTCF gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to Inborn genetic diseases.

*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.Pro378Leu |
| Coding change (HGVS c.) | c.1133C>T |
| MANE Select transcript | [NM_006565](https://www.ncbi.nlm.nih.gov/nuccore/NM_006565) |
| dbSNP | [rs2142847512](https://www.ncbi.nlm.nih.gov/snp/rs2142847512/) |
| Variant type | single nucleotide variant |
| Location | chr16:67620743-67620743 (GRCh38) |
| ClinVar | [VCV1325781](https://www.ncbi.nlm.nih.gov/clinvar/variation/1325781/) |

**All HGVS expressions:** `NC_000016.10:g.67620743C>T`, `NC_000016.9:g.67654646C>T`, `NG_033892.1:g.63337C>T`, `NM_001191022.2:c.149C>T`, `NM_001363916.2:c.1133C>T`, `NM_006565.4:c.1133C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9987) — concordant with the pathogenic call
- REVEL 0.526 (indeterminate)
- SaProt LLR -12.842 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 7.685, GERP 2.05, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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.*
- Regional missense constraint: **o/e 0.24** across the covering region of the MANE Select transcript (67,611,510–67,621,571), spanning 10,061 bp — the region is depleted of missense variation. Chi-square p 3.4e-38. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.000256%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,169,718 in the highest group · 3/1,448,326 alleles overall — very rare (popmax 0.000256%, nfe).

*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 **378** 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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-09-20.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely pathogenic).

**Submission history:** 4 submissions (2019–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Leipzig Medical Center | Pathogenic | criteria provided, single submitter | clinical testing | 2019-12-21 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-08-29 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-20 |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Inborn genetic diseases, CTCF-related neurodevelopmental disorder, 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.Pro378=](/variant/ctcf-p-pro378), [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 1325781). 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.*