# NM_004380.3(CREBBP):c.6005_6006del (p.Val2002fs)

https://sugi.bio/variant/crebbp-p-val2002fs

## Summary

**CREBBP p.Val2002fs (c.6005_6006del)** is classified **Pathogenic** in CREBBP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-31). No gnomAD frequency available for this variant; Associated with Rubinstein-Taybi syndrome due to CREBBP mutations.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2548347574 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CREBBP gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Rubinstein-Taybi syndrome due to CREBBP mutations.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017534/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CREBBP](https://sugi.bio/atlas/gene/CREBBP/) |
| Protein change (HGVS p.) | p.Val2002fs |
| Coding change (HGVS c.) | c.6005_6006del |
| MANE Select transcript | [NM_004380](https://www.ncbi.nlm.nih.gov/nuccore/NM_004380) |
| dbSNP | [rs2548347574](https://www.ncbi.nlm.nih.gov/snp/rs2548347574/) |
| Variant type | Microsatellite |
| Location | chr16:3729041-3729042 (GRCh38) |
| ClinVar | [VCV1805452](https://www.ncbi.nlm.nih.gov/clinvar/variation/1805452/) |

**All HGVS expressions:** `LRG_1426:g.156670TG[1]`, `LRG_1426t1:c.6005_6006del`, `NC_000016.10:g.3729041CA[1]`, `NC_000016.9:g.3779042CA[1]`, `NG_009873.2:g.156670TG[1]`, `NM_001079846.1:c.5891_5892del`, `NM_004380.3:c.6005_6006del`

## 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 7.477, GERP -0.346, 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 0.101, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (31 of 31)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- 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}

**CREBBP** population constraint: LOEUF 0.101, pLI 1, missense-Z 4.7763; 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):

- **Rubinstein-Taybi syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **2002** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 54.31, 20% of residues very-high.

**144 experimental structure(s)** (PDB): [1JSP](https://www.rcsb.org/structure/1JSP), [1LIQ](https://www.rcsb.org/structure/1LIQ), [1RDT](https://www.rcsb.org/structure/1RDT), [1WO3](https://www.rcsb.org/structure/1WO3), [1WO4](https://www.rcsb.org/structure/1WO4), [1WO5](https://www.rcsb.org/structure/1WO5) — incl. mutant structure 1WO3.

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

*Describes the biological roles of CREBBP (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:** CREBBP's established molecular role includes transcription coactivator binding. p.Val2002fs falls in the disordered region. In Reactome, CREBBP is annotated in disease pathway(s) including **Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants**, **Constitutive Signaling by NOTCH1 PEST Domain Mutants**.

**Disease mechanism (Reactome):** CREBBP loss or alteration is curated in [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862), [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606), [Evasion by RSV of host interferon responses](https://reactome.org/content/detail/R-HSA-9833109).

### Pathways affected {#pathways}

CREBBP participates in **57 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862) | curated |
| ⚕ [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606) | curated |
| ⚕ [Evasion by RSV of host interferon responses](https://reactome.org/content/detail/R-HSA-9833109) | curated |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | curated |
| [Activation of gene expression by SREBF (SREBP)](https://reactome.org/content/detail/R-HSA-2426168) | curated |
| [Activation of the TFAP2 (AP-2) family of transcription factors](https://reactome.org/content/detail/R-HSA-8866907) | curated |
| [Attenuation phase](https://reactome.org/content/detail/R-HSA-3371568) | curated |
| [CD209 (DC-SIGN) signaling](https://reactome.org/content/detail/R-HSA-5621575) | curated |
| [Cytoprotection by HMOX1](https://reactome.org/content/detail/R-HSA-9707564) | curated |
| [Estrogen-dependent gene expression](https://reactome.org/content/detail/R-HSA-9018519) | curated |
| [Formation of the beta-catenin:TCF transactivating complex](https://reactome.org/content/detail/R-HSA-201722) | curated |
| [LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production](https://reactome.org/content/detail/R-HSA-3134973) | curated |
| [NFE2L2 regulates pentose phosphate pathway genes](https://reactome.org/content/detail/R-HSA-9818028) | curated |
| [NFE2L2 regulating ER-stress associated genes](https://reactome.org/content/detail/R-HSA-9818035) | curated |
| [NFE2L2 regulating MDR associated enzymes](https://reactome.org/content/detail/R-HSA-9818032) | curated |
| [NFE2L2 regulating inflammation associated genes](https://reactome.org/content/detail/R-HSA-9818026) | curated |
| [NFE2L2 regulating tumorigenic genes](https://reactome.org/content/detail/R-HSA-9818030) | curated |
| [NOTCH4 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-9013695) | curated |
| [NPAS4 regulates expression of target genes](https://reactome.org/content/detail/R-HSA-9768919) | curated |
| [Notch-HLH transcription pathway](https://reactome.org/content/detail/R-HSA-350054) | curated |
| [Nuclear events mediated by NFE2L2](https://reactome.org/content/detail/R-HSA-9759194) | curated |
| [RUNX1 regulates transcription of genes involved in differentiation of myeloid cells](https://reactome.org/content/detail/R-HSA-8939246) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [Regulation of gene expression by Hypoxia-inducible Factor](https://reactome.org/content/detail/R-HSA-1234158) | curated |
| [Regulation of lipid metabolism by PPARalpha](https://reactome.org/content/detail/R-HSA-400206) | curated |
| [TP53 Regulates Transcription of Genes Involved in Cytochrome C Release](https://reactome.org/content/detail/R-HSA-6803204) | curated |
| [TRAF3-dependent IRF activation pathway](https://reactome.org/content/detail/R-HSA-918233) | curated |
| [TRAF6 mediated IRF7 activation](https://reactome.org/content/detail/R-HSA-933541) | curated |
| [Transcriptional activation of mitochondrial biogenesis](https://reactome.org/content/detail/R-HSA-2151201) | curated |
| [Activation of anterior HOX genes in hindbrain development during early embryogenesis](https://reactome.org/content/detail/R-HSA-5617472) | electronic |
| [BMAL1:CLOCK,NPAS2 activates circadian expression](https://reactome.org/content/detail/R-HSA-1368108) | electronic |
| [CHD6, CHD7, CHD8, CHD9 subfamily](https://reactome.org/content/detail/R-HSA-9943962) | electronic |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [Expression of BMAL (ARNTL), CLOCK, and NPAS2](https://reactome.org/content/detail/R-HSA-9931509) | electronic |
| [FOXO-mediated transcription of cell death genes](https://reactome.org/content/detail/R-HSA-9614657) | electronic |
| [Formation of paraxial mesoderm](https://reactome.org/content/detail/R-HSA-9793380) | electronic |
| [HATs acetylate histones](https://reactome.org/content/detail/R-HSA-3214847) | electronic |
| [Heme signaling](https://reactome.org/content/detail/R-HSA-9707616) | electronic |
| [MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis](https://reactome.org/content/detail/R-HSA-9841922) | electronic |
| [NFE2L2 regulating anti-oxidant/detoxification enzymes](https://reactome.org/content/detail/R-HSA-9818027) | electronic |
| [NOTCH1 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-2122947) | electronic |
| [NOTCH3 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-9013508) | electronic |
| [PPARA activates gene expression](https://reactome.org/content/detail/R-HSA-1989781) | electronic |
| [Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes](https://reactome.org/content/detail/R-HSA-9931510) | electronic |
| [Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters](https://reactome.org/content/detail/R-HSA-9931512) | electronic |
| [Pre-NOTCH Transcription and Translation](https://reactome.org/content/detail/R-HSA-1912408) | electronic |
| [RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression](https://reactome.org/content/detail/R-HSA-9933387) | electronic |
| [RUNX3 regulates NOTCH signaling](https://reactome.org/content/detail/R-HSA-8941856) | electronic |
| [Regulation of FOXO transcriptional activity by acetylation](https://reactome.org/content/detail/R-HSA-9617629) | electronic |
| [Regulation of NFE2L2 gene expression](https://reactome.org/content/detail/R-HSA-9818749) | electronic |
| [Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells](https://reactome.org/content/detail/R-HSA-210744) | electronic |
| [SUMOylation of transcription cofactors](https://reactome.org/content/detail/R-HSA-3899300) | electronic |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |
| [The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex](https://reactome.org/content/detail/R-HSA-9931521) | electronic |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | electronic |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | electronic |
| [Zygotic genome activation (ZGA)](https://reactome.org/content/detail/R-HSA-9819196) | electronic |

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

**Molecular function:** transcription coactivator binding, p53 binding, chromatin binding, damaged DNA binding, transcription coactivator activity, transcription corepressor activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, canonical NF-kappaB signal transduction, negative regulation of transcription by RNA polymerase I, positive regulation of transforming growth factor beta receptor signaling pathway, cellular response to nutrient levels, positive regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-31.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2022-03-31 |

## Associated conditions {#conditions}

[Rubinstein-Taybi syndrome due to CREBBP mutations](https://sugi.bio/atlas/disease/rubinstein-taybi-syndrome-due-to-crebbp-mutations/).

**Reported phenotype names (ClinVar):** Rubinstein-Taybi syndrome due to CREBBP mutations, BROAD THUMBS AND GREAT TOES, CHARACTERISTIC FACIES, AND IMPAIRED INTELLECTUAL DEVELOPMENT, RUBINSTEIN SYNDROME, BROAD THUMB-HALLUX SYNDROME, RUBINSTEIN-TAYBI SYNDROME 1, INCOMPLETE, Rubinstein-Taybi syndrome 1, CREBBP-Related Rubinstein-Taybi Syndrome.

## Similar variants {#similar}

Related CREBBP variant pages (same residue, condition, or type): [CREBBP p.Leu1882fs](/variant/crebbp-p-leu1882fs), [CREBBP p.Phe1633del](/variant/crebbp-p-phe1633del), [CREBBP p.Ser1680del](/variant/crebbp-p-ser1680del), [CREBBP p.Ser302fs](/variant/crebbp-p-ser302fs), [CREBBP p.Leu1549fs](/variant/crebbp-p-leu1549fs), [CREBBP p.Leu521fs](/variant/crebbp-p-leu521fs), [CREBBP p.Leu869fs](/variant/crebbp-p-leu869fs), [CREBBP c.3064_3066del](/variant/crebbp-c-3064-3066del).

### 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 1805452). 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.*