# NM_006565.4(CTCF):c.1586A>T (p.Asp529Val)

https://sugi.bio/variant/ctcf-p-asp529val

## Summary

**CTCF p.Asp529Val (c.1586A>T)** is classified **Uncertain significance** in CTCF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-02). AlphaMissense: likely pathogenic (0.9309); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CTCF gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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.Asp529Val |
| Coding change (HGVS c.) | c.1586A>T |
| MANE Select transcript | [NM_006565](https://www.ncbi.nlm.nih.gov/nuccore/NM_006565) |
| Variant type | single nucleotide variant |
| Location | chr16:67628437-67628437 (GRCh38) |
| ClinVar | [VCV3372932](https://www.ncbi.nlm.nih.gov/clinvar/variation/3372932/) |

**All HGVS expressions:** `NC_000016.10:g.67628437A>T`, `NC_000016.9:g.67662340A>T`, `NG_033892.1:g.71031A>T`, `NM_001191022.2:c.602A>T`, `NM_001363916.2:c.1586A>T`, `NM_006565.4:c.1586A>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9309)
- REVEL 0.427 (indeterminate)
- SaProt LLR -11.104 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 11.099, GERP -0.003, 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 0.44** across the covering region of the MANE Select transcript (67,621,572–67,629,428), spanning 7,856 bp. Chi-square p 2.7e-14. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>G, Δ0.43 donor gain), 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}

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

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-02.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-02 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CTCF variant pages (same residue, condition, or type): [CTCF p.Asp529Asn](/variant/ctcf-p-asp529asn), [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 3372932). 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.*