# NM_001904.4(CTNNB1):c.2118C>T (p.Pro706=)

https://sugi.bio/variant/ctnnb1-p-pro706

## Summary

**CTNNB1 p.Pro706= (c.2118C>T)** is classified **Likely benign** in CTNNB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-30). Ultra-rare (popmax 0.0165%, mid).

**At a glance:** Likely benign · review: Single submitter · rsID rs1364710473 · 1 submitter · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the CTNNB1 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 | [CTNNB1](https://sugi.bio/atlas/gene/CTNNB1/) |
| Protein change (HGVS p.) | p.Pro706= |
| Coding change (HGVS c.) | c.2118C>T |
| MANE Select transcript | [NM_001904](https://www.ncbi.nlm.nih.gov/nuccore/NM_001904) |
| dbSNP | [rs1364710473](https://www.ncbi.nlm.nih.gov/snp/rs1364710473/) |
| Variant type | single nucleotide variant |
| Location | chr3:41238057-41238057 (GRCh38) |
| ClinVar | [VCV1574969](https://www.ncbi.nlm.nih.gov/clinvar/variation/1574969/) |

**All HGVS expressions:** `LRG_1108:g.43607C>T`, `LRG_1108t1:c.2118C>T`, `NC_000003.11:g.41279548C>T`, `NC_000003.12:g.41238057C>T`, `NG_013302.2:g.43607C>T`, `NM_001098209.2:c.2118C>T`, `NM_001098210.2:c.2118C>T`, `NM_001330729.2:c.2097C>T`, `NM_001904.4:c.2118C>T`

## 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 0.087, GERP -1.42, phastCons 0.91 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.871**. 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 **0.0165%** (mid) · FAF95 7.9e-05% · FAF99 5.4e-05% · 1/6,062 in the highest group · 7/1,461,524 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| African / African-American | 0.00133% | 75,010 |
| South Asian | 0.0011% | 91,072 |
| European (non-Finnish) | 0.000339% | 294,935 |

*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}

**CTNNB1** population constraint: LOEUF 0.139, pLI 1, missense-Z 5.7223; 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):

- **CTNNB1-related neurodevelopmental disorder and/or vitreoretinopathy** — Definitive (AD)

## Protein context {#protein}

Residue **706** lies in the 'disordered' region; a UniProt-annotated variant site (in nedsdv; the patient also manifest features of exudative vitreoretinopathy).

AlphaFold model confidence (whole protein): pLDDT 81.02, 63% of residues very-high.

**50 experimental structure(s)** (PDB): [1G3J](https://www.rcsb.org/structure/1G3J), [1JDH](https://www.rcsb.org/structure/1JDH), [1JPW](https://www.rcsb.org/structure/1JPW), [1LUJ](https://www.rcsb.org/structure/1LUJ), [1P22](https://www.rcsb.org/structure/1P22), [1QZ7](https://www.rcsb.org/structure/1QZ7) — incl. mutant structure 6O9C.

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

*Describes the biological roles of CTNNB1 (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:** CTNNB1's established molecular role includes transcription corepressor binding. p.Pro706= falls in the disordered region. In Reactome, CTNNB1 is annotated in disease pathway(s) including **CTNNB1 S33 mutants aren't phosphorylated**, **CTNNB1 S37 mutants aren't phosphorylated**.

**Disease mechanism (Reactome):** CTNNB1 loss or alteration is curated in [CTNNB1 S33 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358747), [CTNNB1 S37 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358749), [CTNNB1 S45 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358751).

### Pathways affected {#pathways}

CTNNB1 participates in **46 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [CTNNB1 S33 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358747) | curated |
| ⚕ [CTNNB1 S37 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358749) | curated |
| ⚕ [CTNNB1 S45 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358751) | curated |
| ⚕ [CTNNB1 T41 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358752) | curated |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| ⚕ [InlA-mediated entry of Listeria monocytogenes into host cells](https://reactome.org/content/detail/R-HSA-8876493) | curated |
| ⚕ [Signaling by GSK3beta mutants](https://reactome.org/content/detail/R-HSA-5339716) | curated |
| [Adherens junctions interactions](https://reactome.org/content/detail/R-HSA-418990) | curated |
| [Apoptotic cleavage of cell adhesion  proteins](https://reactome.org/content/detail/R-HSA-351906) | curated |
| [Beta-catenin phosphorylation cascade](https://reactome.org/content/detail/R-HSA-196299) | curated |
| [Binding of TCF/LEF:CTNNB1 to target gene promoters](https://reactome.org/content/detail/R-HSA-4411364) | curated |
| [CHD6, CHD7, CHD8, CHD9 subfamily](https://reactome.org/content/detail/R-HSA-9943962) | curated |
| [Ca2+ pathway](https://reactome.org/content/detail/R-HSA-4086398) | curated |
| [Deactivation of the beta-catenin transactivating complex](https://reactome.org/content/detail/R-HSA-3769402) | curated |
| [Degradation of CDH1](https://reactome.org/content/detail/R-HSA-9766229) | curated |
| [Degradation of beta-catenin by the destruction complex](https://reactome.org/content/detail/R-HSA-195253) | curated |
| [LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production](https://reactome.org/content/detail/R-HSA-3134973) | curated |
| [RHO GTPases activate IQGAPs](https://reactome.org/content/detail/R-HSA-5626467) | curated |
| [RUNX3 regulates WNT signaling](https://reactome.org/content/detail/R-HSA-8951430) | curated |
| [Regulation of CDH1 Function](https://reactome.org/content/detail/R-HSA-9764561) | curated |
| [Regulation of CDH1 posttranslational processing and trafficking to plasma membrane](https://reactome.org/content/detail/R-HSA-9768727) | curated |
| [Regulation of MITF-M-dependent genes involved in cell cycle and proliferation](https://reactome.org/content/detail/R-HSA-9825892) | curated |
| [Regulation of MITF-M-dependent genes involved in pigmentation](https://reactome.org/content/detail/R-HSA-9824585) | curated |
| [Regulation of PD-L1(CD274) transcription](https://reactome.org/content/detail/R-HSA-9909649) | curated |
| [Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)](https://reactome.org/content/detail/R-HSA-381771) | curated |
| [TCF dependent signaling in response to WNT](https://reactome.org/content/detail/R-HSA-201681) | curated |
| [Transcriptional Regulation by VENTX](https://reactome.org/content/detail/R-HSA-8853884) | curated |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | curated |
| [VEGFR2 mediated vascular permeability](https://reactome.org/content/detail/R-HSA-5218920) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | electronic |
| [CDH11 homotypic and heterotypic interactions](https://reactome.org/content/detail/R-HSA-9833576) | electronic |
| [Cardiogenesis](https://reactome.org/content/detail/R-HSA-9733709) | electronic |
| [Disassembly of the destruction complex and recruitment of AXIN to the membrane](https://reactome.org/content/detail/R-HSA-4641262) | electronic |
| [Formation of axial mesoderm](https://reactome.org/content/detail/R-HSA-9796292) | electronic |
| [Formation of definitive endoderm](https://reactome.org/content/detail/R-HSA-9823730) | electronic |
| [Formation of paraxial mesoderm](https://reactome.org/content/detail/R-HSA-9793380) | electronic |
| [Formation of the beta-catenin:TCF transactivating complex](https://reactome.org/content/detail/R-HSA-201722) | electronic |
| [Formation of the nephric duct](https://reactome.org/content/detail/R-HSA-9830364) | electronic |
| [Germ layer formation at gastrulation](https://reactome.org/content/detail/R-HSA-9754189) | electronic |
| [High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells](https://reactome.org/content/detail/R-HSA-9856530) | electronic |
| [Myogenesis](https://reactome.org/content/detail/R-HSA-525793) | electronic |
| [Regulation of CDH11 function](https://reactome.org/content/detail/R-HSA-9762292) | electronic |
| [Regulation of CDH19 Expression and Function](https://reactome.org/content/detail/R-HSA-9764302) | electronic |
| [SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)](https://reactome.org/content/detail/R-HSA-9958810) | electronic |
| [Somitogenesis](https://reactome.org/content/detail/R-HSA-9824272) | electronic |
| [Specification of the neural plate border](https://reactome.org/content/detail/R-HSA-9834899) | electronic |

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

**Molecular function:** transcription corepressor binding, transcription coactivator activity, signaling receptor binding, nuclear receptor binding, enzyme binding, kinase binding.

**Biological process:** protein polyubiquitination, osteoblast differentiation, cell adhesion, epidermal growth factor receptor signaling pathway, negative regulation of cell population proliferation, response to xenobiotic stimulus.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-30.

**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 | 2021-07-30 |

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

## Same-residue context {#hotspot}

Residue **706** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CTNNB1 p.Pro706fs](/variant/ctnnb1-p-pro706fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CTNNB1 variant pages (same residue, condition, or type): [CTNNB1 p.Pro706fs](/variant/ctnnb1-p-pro706fs), [CTNNB1 c.1081+1G>T](/variant/ctnnb1-c-1081-plus-1g-t), [CTNNB1 c.1082-1G>C](/variant/ctnnb1-c-1082-minus-1g-c), [CTNNB1 c.735-1G>C](/variant/ctnnb1-c-735-minus-1g-c), [CTNNB1 p.Arg474Ter](/variant/ctnnb1-p-arg474ter), [CTNNB1 p.Arg515Ter](/variant/ctnnb1-p-arg515ter), [CTNNB1 p.Arg535Ter](/variant/ctnnb1-p-arg535ter), [CTNNB1 p.Arg587Ter](/variant/ctnnb1-p-arg587ter).

### 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 1574969). 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.*