# NM_000038.6(APC):c.295C>A (p.Arg99=)

https://sugi.bio/variant/apc-p-arg99

## Summary

**APC p.Arg99= (c.295C>A)** is classified **Conflicting classifications of pathogenicity** in APC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-17). Absent from gnomAD v4.1; Associated with familial adenomatous polyposis 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs139196838 · 5 submitters · 3 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the APC gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 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.Arg99= |
| Coding change (HGVS c.) | c.295C>A |
| MANE Select transcript | [NM_000038](https://www.ncbi.nlm.nih.gov/nuccore/NM_000038) |
| dbSNP | [rs139196838](https://www.ncbi.nlm.nih.gov/snp/rs139196838/) |
| Variant type | single nucleotide variant |
| Location | chr5:112767263-112767263 (GRCh38) |
| ClinVar | [VCV469782](https://www.ncbi.nlm.nih.gov/clinvar/variation/469782/) |

**All HGVS expressions:** `LRG_130:g.79743C>A`, `NC_000005.10:g.112767263C>A`, `NC_000005.9:g.112102960C>A`, `NG_008481.4:g.79743C>A`, `NM_000038.6:c.295C>A`, `NM_001127510.3:c.295C>A`, `NM_001127511.3:c.325C>A`, `NM_001354895.2:c.295C>A`, `NM_001354896.2:c.295C>A`, `NM_001354897.2:c.325C>A`, `NM_001354898.2:c.220C>A`, `NM_001354899.2:c.295C>A`, `NM_001354900.2:c.118C>A`, `NM_001354901.2:c.118C>A`, `NM_001354902.2:c.325C>A`, `NM_001354903.2:c.295C>A`, `NM_001354904.2:c.220C>A`, `NM_001354905.2:c.118C>A`, `NM_001354906.2:c.-741C>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.49) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 4.889, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 21.2**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.49**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.49**, donor gain **0.00**.
- Pangolin: Δ**0.24** (gain), gain 0.24 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is 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}

**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 **99** lies in a UniProt-annotated variant site (in fap1; benign).

**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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-08-17.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Likely Benign, 1 Benign, 1 Likely benign).

**Submission history:** 5 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-17 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-11-20 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2024-02-22 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2022-08-31 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-05 |

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

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

## Same-residue context {#hotspot}

Residue **99** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [APC p.Arg99fs](/variant/apc-p-arg99fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related APC variant pages (same residue, condition, or type): [APC p.Arg99Trp](/variant/apc-p-arg99trp), [APC p.Arg99Gln](/variant/apc-p-arg99gln), [APC p.Arg99Gly](/variant/apc-p-arg99gly), [APC p.Arg99Leu](/variant/apc-p-arg99leu), [APC p.Arg99fs](/variant/apc-p-arg99fs), [APC c.1312+3A>C](/variant/apc-c-1312-plus-3a-c), [APC c.1312+3A>G](/variant/apc-c-1312-plus-3a-g), [APC c.1312+5G>A](/variant/apc-c-1312-plus-5g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 469782). 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.*