# NM_004655.4(AXIN2):c.1284C>G (p.Ser428=)

https://sugi.bio/variant/axin2-p-ser428

## Summary

**AXIN2 p.Ser428= (c.1284C>G)** is classified **Likely benign** in AXIN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-26). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

**At a glance:** Likely benign · review: Multiple submitters · 2 submitters · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the AXIN2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to hereditary neoplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AXIN2](https://sugi.bio/atlas/gene/AXIN2/) |
| Protein change (HGVS p.) | p.Ser428= |
| Coding change (HGVS c.) | c.1284C>G |
| MANE Select transcript | [NM_004655](https://www.ncbi.nlm.nih.gov/nuccore/NM_004655) |
| Variant type | single nucleotide variant |
| Location | chr17:65537752-65537752 (GRCh38) |
| ClinVar | [VCV3980804](https://www.ncbi.nlm.nih.gov/clinvar/variation/3980804/) |

**All HGVS expressions:** `LRG_296:g.28871C>G`, `LRG_296t1:c.1284C>G`, `NC_000017.10:g.63533870G>C`, `NC_000017.11:g.65537752G>C`, `NG_012142.1:g.28871C>G`, `NM_001363813.1:c.1284C>G`, `NM_004655.4:c.1284C>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 -3.455, GERP -3.67 — fast-evolving / accelerated position
- CADD: **PHRED 0.297**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.37 acceptor 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}

**AXIN2** population constraint: LOEUF 0.397, pLI 0.99999, missense-Z -0.012915; 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):

- **oligodontia-cancer predisposition syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **428** lies in the 'disordered' region; the 'interaction with beta-catenin' region.

AlphaFold model confidence (whole protein): pLDDT 61.71, 24% of residues very-high.

**1 experimental structure(s)** (PDB): [8HEO](https://www.rcsb.org/structure/8HEO).

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

*Describes the biological roles of AXIN2 (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:** AXIN2's established molecular role includes enzyme binding. p.Ser428= falls in the disordered region.


### Pathways affected {#pathways}

AXIN2 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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 |
| [Degradation of AXIN](https://reactome.org/content/detail/R-HSA-4641257) | curated |
| [TCF dependent signaling in response to WNT](https://reactome.org/content/detail/R-HSA-201681) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |

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

**Molecular function:** enzyme binding, ubiquitin protein ligase binding.

**Biological process:** intracellular protein localization, positive regulation of epithelial to mesenchymal transition, regulation of mismatch repair, odontogenesis, maintenance of DNA repeat elements, mRNA stabilization.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-26.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-03 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [oligodontia-cancer predisposition syndrome](https://sugi.bio/atlas/disease/oligodontia-cancer-predisposition-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Oligodontia-cancer predisposition syndrome, Tumor predisposition, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, TOOTH AGENESIS-COLORECTAL CANCER SYNDROME.

## Same-residue context {#hotspot}

Residue **428** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [AXIN2 p.Ser428fs](/variant/axin2-p-ser428fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AXIN2 variant pages (same residue, condition, or type): [AXIN2 p.Ser428Cys](/variant/axin2-p-ser428cys), [AXIN2 p.Ser428Phe](/variant/axin2-p-ser428phe), [AXIN2 p.Ser428Pro](/variant/axin2-p-ser428pro), [AXIN2 p.Ser428Ala](/variant/axin2-p-ser428ala), [AXIN2 p.Ser428Tyr](/variant/axin2-p-ser428tyr), [AXIN2 p.Ser428fs](/variant/axin2-p-ser428fs), [AXIN2 c.1060-1G>C](/variant/axin2-c-1060-minus-1g-c), [AXIN2 c.1200+1G>A](/variant/axin2-c-1200-plus-1g-a).

### 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 3980804). 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.*