# NM_004379.5(CREB1):c.243A>G (p.Pro81=)

https://sugi.bio/variant/creb1-p-pro81

## Summary

**CREB1 p.Pro81= (c.243A>G)** is classified **Likely benign** in CREB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-08-04). Very rare (popmax 0.000254%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs758723693 · 1 submitter · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the CREB1 gene that is classified as likely benign — not considered disease-causing, 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 | [CREB1](https://sugi.bio/atlas/gene/CREB1/) |
| Protein change (HGVS p.) | p.Pro81= |
| Coding change (HGVS c.) | c.243A>G |
| MANE Select transcript | [NM_004379](https://www.ncbi.nlm.nih.gov/nuccore/NM_004379) |
| dbSNP | [rs758723693](https://www.ncbi.nlm.nih.gov/snp/rs758723693/) |
| Variant type | single nucleotide variant |
| Location | chr2:207560354-207560354 (GRCh38) |
| ClinVar | [VCV718069](https://www.ncbi.nlm.nih.gov/clinvar/variation/718069/) |

**All HGVS expressions:** `NC_000002.11:g.208425078A>G`, `NC_000002.12:g.207560354A>G`, `NG_023299.1:g.35463A>G`, `NM_001320793.3:c.243A>G`, `NM_001371426.1:c.243A>G`, `NM_001371427.1:c.243A>G`, `NM_001371428.1:c.123A>G`, `NM_004379.5:c.243A>G`, `NM_134442.5:c.243A>G`, `NR_135473.2:n.424A>G`, `NR_163946.1:n.424A>G`, `NR_163947.1:n.308A>G`

## Computational & population evidence {#evidence}

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

- **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 6.192, GERP 1.84, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.32**. 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.*
- 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 **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,874 in the highest group · 3/1,613,928 alleles overall — very rare (popmax 0.000254%, 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}

**CREB1** population constraint: LOEUF 0.189, pLI 1, missense-Z 3.5959. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 62.38, 18% of residues very-high.

**4 experimental structure(s)** (PDB): [2LXT](https://www.rcsb.org/structure/2LXT), [5ZK1](https://www.rcsb.org/structure/5ZK1), [5ZKO](https://www.rcsb.org/structure/5ZKO), [7TBH](https://www.rcsb.org/structure/7TBH).

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

*Describes the biological roles of CREB1 (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:** CREB1's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. In Reactome, CREB1 is annotated in disease pathway(s) including **ADORA2B mediated anti-inflammatory cytokines production**, **Constitutive Signaling by AKT1 E17K in Cancer**.

**Disease mechanism (Reactome):** CREB1 loss or alteration is curated in [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821), [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400), [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323).

### Pathways affected {#pathways}

CREB1 participates in **27 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [ADORA2B mediated anti-inflammatory cytokines production](https://reactome.org/content/detail/R-HSA-9660821) | other |
| ⚕ [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400) | other |
| ⚕ [FCGR3A-mediated IL10 synthesis](https://reactome.org/content/detail/R-HSA-9664323) | other |
| ⚕ [HCMV Early Events](https://reactome.org/content/detail/R-HSA-9609690) | other |
| [AKT phosphorylates targets in the nucleus](https://reactome.org/content/detail/R-HSA-198693) | other |
| [CREB phosphorylation](https://reactome.org/content/detail/R-HSA-199920) | other |
| [CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling](https://reactome.org/content/detail/R-HSA-442742) | other |
| [CREB1 phosphorylation through the activation of Adenylate Cyclase](https://reactome.org/content/detail/R-HSA-442720) | other |
| [CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde](https://reactome.org/content/detail/R-HSA-442729) | other |
| [CaMK IV-mediated phosphorylation of CREB](https://reactome.org/content/detail/R-HSA-111932) | other |
| [Estrogen-dependent nuclear events downstream of ESR-membrane signaling](https://reactome.org/content/detail/R-HSA-9634638) | other |
| [Expression of BMAL (ARNTL), CLOCK, and NPAS2](https://reactome.org/content/detail/R-HSA-9931509) | other |
| [Gastrin-CREB signalling pathway via PKC and MAPK](https://reactome.org/content/detail/R-HSA-881907) | other |
| [Heme signaling](https://reactome.org/content/detail/R-HSA-9707616) | other |
| [MECP2 regulates neuronal receptors and channels](https://reactome.org/content/detail/R-HSA-9022699) | other |
| [MECP2 regulates transcription factors](https://reactome.org/content/detail/R-HSA-9022707) | other |
| [MECP2 regulates transcription of neuronal ligands](https://reactome.org/content/detail/R-HSA-9022702) | other |
| [NCAM signaling for neurite out-growth](https://reactome.org/content/detail/R-HSA-375165) | other |
| [NGF-stimulated transcription](https://reactome.org/content/detail/R-HSA-9031628) | other |
| [NOTCH2 intracellular domain regulates transcription](https://reactome.org/content/detail/R-HSA-2197563) | other |
| [PKA-mediated phosphorylation of CREB](https://reactome.org/content/detail/R-HSA-111931) | other |
| [Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes](https://reactome.org/content/detail/R-HSA-9931510) | other |
| [Regulation of MECP2 expression and activity](https://reactome.org/content/detail/R-HSA-9022692) | other |
| [Regulation of MITF-M-dependent genes involved in pigmentation](https://reactome.org/content/detail/R-HSA-9824585) | other |
| [Transcriptional activation of mitochondrial biogenesis](https://reactome.org/content/detail/R-HSA-2151201) | other |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | other |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | other |

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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription factor activity, RNA polymerase II-specific, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA-binding transcription factor activity, enzyme binding, cAMP response element binding.

**Biological process:** protein phosphorylation, obsolete negative regulation of transcription by competitive promoter binding, response to purine-containing compound, mRNA transcription by RNA polymerase II, positive regulation of transcription by RNA polymerase II, cAMP/PKA signal transduction.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2017-08-04.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2017-08-04 |

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

## Similar variants {#similar}

Related CREB1 variant pages (same residue, condition, or type): [CREB1 p.Ala72=](/variant/creb1-p-ala72), [CREB1 p.Thr194=](/variant/creb1-p-thr194), [CREB1 p.Ala148Thr](/variant/creb1-p-ala148thr), [CREB1 p.Ala150Ser](/variant/creb1-p-ala150ser), [CREB1 p.Ala176Glu](/variant/creb1-p-ala176glu), [CREB1 p.Ala259Thr](/variant/creb1-p-ala259thr), [CREB1 p.Ala43Glu](/variant/creb1-p-ala43glu), [CREB1 p.Ala46Gly](/variant/creb1-p-ala46gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 718069). 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.*