# NM_000038.6(APC):c.421_422del (p.Arg141fs)

https://sugi.bio/variant/apc-p-arg141fs

## Summary

**APC p.Arg141fs (c.421_422del)** is classified **Pathogenic** in APC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-30). No gnomAD frequency available for this variant; Associated with familial adenomatous polyposis 1.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1554069850 · 4 submitters · 2 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 familial adenomatous polyposis 1.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Adult |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 12 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | APC is a diagnostic-grade gene on 16 Genomics England panels |

**Commonly reported features of Familial adenomatous polyposis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Colon cancer — Very frequent (99-80%)
- Adenomatous colonic polyposis — Very frequent (99-80%)
- Neoplasm of the gastrointestinal tract — Very frequent (99-80%)
- Congenital hypertrophy of retinal pigment epithelium — Very frequent (99-80%)
- Desmoid tumors — Very frequent (99-80%)
- Colorectal polyposis — Very frequent (99-80%)
- Abnormality of the dentition — Frequent (79-30%)
- Diarrhea — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025282/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.Arg141fs |
| Coding change (HGVS c.) | c.421_422del |
| MANE Select transcript | [NM_000038](https://www.ncbi.nlm.nih.gov/nuccore/NM_000038) |
| dbSNP | [rs1554069850](https://www.ncbi.nlm.nih.gov/snp/rs1554069850/) |
| Variant type | Microsatellite |
| Location | chr5:112767385-112767386 (GRCh38) |
| ClinVar | [VCV469954](https://www.ncbi.nlm.nih.gov/clinvar/variation/469954/) |

**All HGVS expressions:** `LRG_130:g.79865AG[2]`, `NC_000005.10:g.112767385AG[2]`, `NC_000005.9:g.112103082AG[2]`, `NG_008481.4:g.79865AG[2]`, `NM_000038.5:c.421_422del`, `NM_000038.5:c.421_422delAG`, `NM_000038.6:c.421_422del`, `NM_001127510.3:c.421_422del`, `NM_001127511.3:c.451_452del`, `NM_001354895.2:c.421_422del`, `NM_001354896.2:c.421_422del`, `NM_001354897.2:c.451_452del`, `NM_001354898.2:c.346_347del`, `NM_001354899.2:c.421_422del`, `NM_001354900.2:c.244_245del`, `NM_001354901.2:c.244_245del`, `NM_001354902.2:c.451_452del`, `NM_001354903.2:c.421_422del`, `NM_001354904.2:c.346_347del`, `NM_001354905.2:c.244_245del`, `NM_001354906.2:c.-619AG[2]`

## 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 11.18, 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 exon 4 of 16**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite 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, 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):

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

## Protein context {#protein}

Residue **141** lies in an α-helix.

**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 2025-08-30.

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

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-30 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-24 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-12 |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2023-04-25 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Familial adenomatous polyposis 1, not provided, Hereditary cancer-predisposing syndrome, none provided, POLYPOSIS, ADENOMATOUS INTESTINAL, FAMILIAL ADENOMATOUS POLYPOSIS 1, ATTENUATED, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome.

## Same-residue context {#hotspot}

Residue **141** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [APC p.Arg141Ser](/variant/apc-p-arg141ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related APC variant pages (same residue, condition, or type): [APC p.Arg141Lys](/variant/apc-p-arg141lys), [APC p.Arg141Thr](/variant/apc-p-arg141thr), [APC p.Arg141Ser](/variant/apc-p-arg141ser), [APC p.Arg141=](/variant/apc-p-arg141), [APC p.Arg141Gly](/variant/apc-p-arg141gly), [APC c.531+5_531+8del](/variant/apc-c-531-plus-5-531-plus-8del), [APC p.Gln2600fs](/variant/apc-p-gln2600fs), [APC p.Glu2655fs](/variant/apc-p-glu2655fs).

### 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 469954). 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.*