# NM_004380.3(CREBBP):c.6677C>T (p.Ala2226Val)

https://sugi.bio/variant/crebbp-p-ala2226val

## Summary

**CREBBP p.Ala2226Val (c.6677C>T)** is classified **Conflicting classifications of pathogenicity** in CREBBP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-06-16). AlphaMissense: likely benign (0.123); Very rare (popmax 0.00802%, afr); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs754601626 · 3 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00802%, afr)

## For patients & families {#patients}

This is a change in the CREBBP gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 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 | [CREBBP](https://sugi.bio/atlas/gene/CREBBP/) |
| Protein change (HGVS p.) | p.Ala2226Val |
| Coding change (HGVS c.) | c.6677C>T |
| MANE Select transcript | [NM_004380](https://www.ncbi.nlm.nih.gov/nuccore/NM_004380) |
| dbSNP | [rs754601626](https://www.ncbi.nlm.nih.gov/snp/rs754601626/) |
| Variant type | single nucleotide variant |
| Location | chr16:3728370-3728370 (GRCh38) |
| ClinVar | [VCV1754821](https://www.ncbi.nlm.nih.gov/clinvar/variation/1754821/) |

**All HGVS expressions:** `LRG_1426:g.157344C>T`, `LRG_1426t1:c.6677C>T`, `NC_000016.10:g.3728370G>A`, `NC_000016.9:g.3778371G>A`, `NG_009873.2:g.157344C>T`, `NM_001079846.1:c.6563C>T`, `NM_004380.3:c.6677C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.123)
- REVEL 0.172 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.995 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 9.906, GERP 1.75, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.2**. 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 1.03** across the covering region of the MANE Select transcript (3,727,721–3,728,737), spanning 1,016 bp. Chi-square p 0.52. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for CREBBP (1,535 scored positions, the nearest 572 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00802%** (afr) · FAF95 0.00347% · FAF99 0.00229% · 6/74,858 in the highest group · 20/1,612,616 alleles overall — very rare (popmax 0.00802%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00802% | 12,476 |
| South Asian | 0.0055% | 18,196 |
| East Asian | 0.00223% | 44,836 |
| Admixed American | 0.00167% | 59,868 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,356 |
| European (non-Finnish) | 0.000509% | 196,597 |

*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 3/3, triplosensitivity 0/3. *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 **2226** 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.Ala2226Val 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-06-16.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely benign).

**Submission history:** 3 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-07-11 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-06-16 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-04-26 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CREBBP variant pages (same residue, condition, or type): [CREBBP p.Ala2226=](/variant/crebbp-p-ala2226), [CREBBP p.Ala2226Gly](/variant/crebbp-p-ala2226gly), [CREBBP p.Arg1786Cys](/variant/crebbp-p-arg1786cys), [CREBBP p.Ala1510Val](/variant/crebbp-p-ala1510val), [CREBBP p.Ala15Gly](/variant/crebbp-p-ala15gly), [CREBBP p.Ala1830Thr](/variant/crebbp-p-ala1830thr), [CREBBP p.Ala2049Pro](/variant/crebbp-p-ala2049pro), [CREBBP p.Ala828Val](/variant/crebbp-p-ala828val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 1754821). 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.*