# NM_000038.6(APC):c.5864del (p.Ala1955fs)

https://sugi.bio/variant/apc-p-ala1955fs

## Summary

**APC p.Ala1955fs (c.5864del)** is classified **Pathogenic** in APC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-20). No gnomAD frequency available for this variant; Associated with hereditary neoplastic syndrome.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1290023611 · 4 submitters · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the APC gene that is considered disease-causing, submitted by 4 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 | [APC](https://sugi.bio/atlas/gene/APC/) |
| Protein change (HGVS p.) | p.Ala1955fs |
| Coding change (HGVS c.) | c.5864del |
| MANE Select transcript | [NM_000038](https://www.ncbi.nlm.nih.gov/nuccore/NM_000038) |
| dbSNP | [rs1290023611](https://www.ncbi.nlm.nih.gov/snp/rs1290023611/) |
| Variant type | Deletion |
| Location | chr5:112841458-112841458 (GRCh38) |
| ClinVar | [VCV1750160](https://www.ncbi.nlm.nih.gov/clinvar/variation/1750160/) |

**All HGVS expressions:** `LRG_130:g.153938del`, `LRG_130t1:c.5864del`, `LRG_130t2:c.5864del`, `LRG_130t3:c.5864del`, `NC_000005.10:g.112841458del`, `NC_000005.9:g.112177155del`, `NG_008481.4:g.153938del`, `NM_000038.6:c.5864del`, `NM_001127510.3:c.5864del`, `NM_001127511.3:c.5810del`, `NM_001354895.2:c.5864del`, `NM_001354896.2:c.5918del`, `NM_001354897.2:c.5894del`, `NM_001354898.2:c.5789del`, `NM_001354899.2:c.5780del`, `NM_001354900.2:c.5741del`, `NM_001354901.2:c.5687del`, `NM_001354902.2:c.5591del`, `NM_001354903.2:c.5561del`, `NM_001354904.2:c.5486del`, `NM_001354905.2:c.5384del`, `NM_001354906.2:c.5015del`, `NM_001407446.1:c.5948delC`, `NM_001407447.1:c.5918delC`, `NM_001407448.1:c.5918delC`, `NM_001407449.1:c.5918delC`, `NM_001407450.1:c.5864delC`, `NM_001407451.1:c.5843delC`, `NM_001407452.1:c.5834delC`, `NM_001407453.1:c.5687delC`, `NM_001407454.1:c.5615delC`, `NM_001407455.1:c.5615delC`, `NM_001407456.1:c.5615delC`, `NM_001407457.1:c.5615delC`, `NM_001407458.1:c.5561delC`, `NM_001407459.1:c.5561delC`, `NM_001407460.1:c.5561delC`, `NM_001407467.1:c.5477delC`, `NM_001407469.1:c.5477delC`, `NM_001407470.1:c.5015delC`, `NM_001407471.1:c.4712delC`, `NM_001407472.1:c.4712delC`, `NR_176365.1:n.5699delC`, `NR_176366.1:n.6118delC`

## 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 10.032, GERP 2.81, 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 0.321, 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 (16 of 16)** — 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 deletion 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}

**APC** population constraint: LOEUF 0.321, pLI 1, missense-Z 0.7981; 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):

- **gastric adenocarcinoma and proximal polyposis of the stomach** — Definitive (AD)
- **classic or attenuated familial adenomatous polyposis** — Definitive (AD)

## Protein context {#protein}


**31 experimental structure(s)** (PDB): [1DEB](https://www.rcsb.org/structure/1DEB), [1EMU](https://www.rcsb.org/structure/1EMU), [1JPP](https://www.rcsb.org/structure/1JPP), [1M5I](https://www.rcsb.org/structure/1M5I), [1T08](https://www.rcsb.org/structure/1T08), [1TH1](https://www.rcsb.org/structure/1TH1).

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

*Describes the biological roles of APC (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:** APC's established molecular role includes beta-catenin binding. In Reactome, APC is annotated in disease pathway(s) including **APC truncation mutants are not K63 polyubiquitinated**, **APC truncation mutants have impaired AXIN binding**.

**Disease mechanism (Reactome):** APC loss or alteration is curated in [APC truncation mutants are not K63 polyubiquitinated](https://reactome.org/content/detail/R-HSA-5467333), [APC truncation mutants have impaired AXIN binding](https://reactome.org/content/detail/R-HSA-5467337), [AXIN missense mutants destabilize the destruction complex](https://reactome.org/content/detail/R-HSA-5467340).

### Pathways affected {#pathways}

APC participates in **15 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [APC truncation mutants are not K63 polyubiquitinated](https://reactome.org/content/detail/R-HSA-5467333) | curated |
| ⚕ [APC truncation mutants have impaired AXIN binding](https://reactome.org/content/detail/R-HSA-5467337) | curated |
| ⚕ [AXIN missense mutants destabilize the destruction complex](https://reactome.org/content/detail/R-HSA-5467340) | curated |
| ⚕ [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 |
| ⚕ [Signaling by GSK3beta mutants](https://reactome.org/content/detail/R-HSA-5339716) | curated |
| ⚕ [Truncations of AMER1 destabilize the destruction complex](https://reactome.org/content/detail/R-HSA-5467348) | curated |
| [Apoptotic cleavage of cellular proteins](https://reactome.org/content/detail/R-HSA-111465) | curated |
| [Beta-catenin phosphorylation cascade](https://reactome.org/content/detail/R-HSA-196299) | curated |
| [Deactivation of the beta-catenin transactivating complex](https://reactome.org/content/detail/R-HSA-3769402) | curated |
| [Degradation of beta-catenin by the destruction complex](https://reactome.org/content/detail/R-HSA-195253) | curated |
| [Ovarian tumor domain proteases](https://reactome.org/content/detail/R-HSA-5689896) | curated |
| [Disassembly of the destruction complex and recruitment of AXIN to the membrane](https://reactome.org/content/detail/R-HSA-4641262) | electronic |

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

**Molecular function:** beta-catenin binding, microtubule binding, protein kinase regulator activity, protein kinase binding, ubiquitin protein ligase binding, gamma-catenin binding.

**Biological process:** mitotic cytokinesis, DNA damage response, negative regulation of microtubule depolymerization, mitotic spindle assembly checkpoint signaling, negative regulation of cell population proliferation, insulin receptor signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-02-20.

**Submitter consensus:** unanimous (4/4 Pathogenic).

**Submission history:** 4 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-15 |
| All of Us Research Program, National Institutes of Health | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-26 |
| Color Diagnostics, LLC DBA Color Health | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-26 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-20 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [familial adenomatous polyposis 1](https://sugi.bio/atlas/disease/familial-adenomatous-polyposis-1/), [classic or attenuated familial adenomatous polyposis](https://sugi.bio/atlas/disease/classic-or-attenuated-familial-adenomatous-polyposis/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Classic or attenuated familial adenomatous polyposis, Familial adenomatous polyposis 1, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition, FAMILIAL ADENOMATOUS POLYPOSIS 1, ATTENUATED, POLYPOSIS, ADENOMATOUS INTESTINAL.

## Similar variants {#similar}

Related APC variant pages (same residue, condition, or type): [APC p.Ala1955Thr](/variant/apc-p-ala1955thr), [APC p.Ala1955=](/variant/apc-p-ala1955), [APC c.1311_1312+1del](/variant/apc-c-1311-1312-plus-1del), [APC c.1312+4_1312+19del](/variant/apc-c-1312-plus-4-1312-plus-19del), [APC p.Glu2172fs](/variant/apc-p-glu2172fs), [APC p.Gly53fs](/variant/apc-p-gly53fs), [APC p.Leu68fs](/variant/apc-p-leu68fs), [APC p.Ser2601fs](/variant/apc-p-ser2601fs).

### 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 1750160). 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.*