# NM_000038.6(APC):c.1959G>A (p.Arg653=)

https://sugi.bio/variant/apc-p-arg653

## Summary

**APC p.Arg653= (c.1959G>A)** is classified **Benign/Likely benign** in APC (ClinVar, Multiple submitters, 30 submitters; last evaluated 2026-05-01). Rare (popmax 0.374%, nfe); Associated with APC-Associated Polyposis Disorders.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs72541809 · 30 submitters · 5 linked conditions · rare (popmax 0.374%, nfe)

## For patients & families {#patients}

This is a change in the APC gene that is classified as benign/likely benign — not considered disease-causing, submitted by 30 submitters, and is linked to APC-Associated Polyposis Disorders.

*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 | [APC](https://sugi.bio/atlas/gene/APC/) |
| Protein change (HGVS p.) | p.Arg653= |
| Coding change (HGVS c.) | c.1959G>A |
| MANE Select transcript | [NM_000038](https://www.ncbi.nlm.nih.gov/nuccore/NM_000038) |
| dbSNP | [rs72541809](https://www.ncbi.nlm.nih.gov/snp/rs72541809/) |
| Variant type | single nucleotide variant |
| Location | chr5:112837553-112837553 (GRCh38) |
| ClinVar | [VCV133524](https://www.ncbi.nlm.nih.gov/clinvar/variation/133524/) |

**All HGVS expressions:** `LRG_130:g.150033G>A`, `LRG_130t1:c.1959G>A`, `NC_000005.10:g.112837553G>A`, `NC_000005.9:g.112173250G>A`, `NG_008481.4:g.150033G>A`, `NM_000038.6:c.1959G>A`, `NM_001127510.3:c.1959G>A`, `NM_001127511.3:c.1905G>A`, `NM_001354895.2:c.1959G>A`, `NM_001354896.2:c.2013G>A`, `NM_001354897.2:c.1989G>A`, `NM_001354898.2:c.1884G>A`, `NM_001354899.2:c.1875G>A`, `NM_001354900.2:c.1836G>A`, `NM_001354901.2:c.1782G>A`, `NM_001354902.2:c.1686G>A`, `NM_001354903.2:c.1656G>A`, `NM_001354904.2:c.1581G>A`, `NM_001354905.2:c.1479G>A`, `NM_001354906.2:c.1110G>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 (below), not from a missing predictor score.
- Conservation: phyloP 4.646, GERP 0.047, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.03**. 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, Δ0.24 acceptor loss), 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 (gnomAD v4.1): grpmax **0.374%** (nfe) · FAF95 0.365% · FAF99 0.361% · 4,405/1,177,136 in the highest group · 6,805/1,610,582 alleles overall — rare (popmax 0.374%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 3.1% | 32 |
| European (non-Finnish) (grpmax) | 0.374% | 267 |
| Remaining individuals (not grpmax-eligible) | 0.34% | 294 |
| Middle Eastern | 0.182% | 550 |
| Admixed American | 0.18% | 555 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.101% | 986 |
| African / African-American | 0.0761% | 1,314 |
| South Asian | 0.0022% | 45,459 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

Residue **653** 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-01.

**Submitter consensus:** conflicting (20 Benign, 9 Likely benign, 1 not provided).

**Submission history:** 30 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ITMI | not provided | no classification provided | reference population | 2013-09-19 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | no assertion criteria provided | research |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2014-01-03 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Benign | no assertion criteria provided | clinical testing |  |
| Sema4, Sema4 | Benign | criteria provided, single submitter | curation | 2021-05-02 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2014-12-12 |
| True Health Diagnostics | Likely benign | no assertion criteria provided | clinical testing | 2017-11-10 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2016-06-20 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing | 2016-11-02 |
| Mendelics | Likely benign | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Benign | no assertion criteria provided | clinical testing |  |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Genetic Services Laboratory, University of Chicago | Benign | criteria provided, single submitter | clinical testing | 2020-02-07 |
| Color Diagnostics, LLC DBA Color Health | Benign | criteria provided, single submitter | clinical testing | 2016-03-17 |
| Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Benign | criteria provided, single submitter | clinical testing | 2022-11-22 |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Benign | criteria provided, single submitter | clinical testing | 2023-07-07 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2024-03-08 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-21 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Likely benign | no assertion criteria provided | clinical testing |  |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely benign | no assertion criteria provided | clinical testing |  |
| Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Benign | criteria provided, single submitter | clinical testing | 2015-10-19 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2024-03-20 |
| Dasa | Benign | criteria provided, single submitter | clinical testing | 2026-01-19 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-05-01 |

## Associated conditions {#conditions}

[APC-Associated Polyposis Disorders](https://sugi.bio/atlas/disease/apc-associated-polyposis-disorders/), [colon carcinoma](https://sugi.bio/atlas/disease/colon-carcinoma/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [classic familial adenomatous polyposis](https://sugi.bio/atlas/disease/classic-familial-adenomatous-polyposis/), [familial adenomatous polyposis 1](https://sugi.bio/atlas/disease/familial-adenomatous-polyposis-1/).

**Reported phenotype names (ClinVar):** APC-Associated Polyposis Disorders, not specified, Hereditary cancer-predisposing syndrome, Familial multiple polyposis syndrome, not provided, Familial adenomatous polyposis 1, Carcinoma of colon, Tumor predisposition, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary.

## Same-residue context {#hotspot}

Residue **653** carries **4 other pathogenic ClinVar variants** — a recurrently-mutated position: [APC p.Arg653Thr](/variant/apc-p-arg653thr), [APC p.Arg653Met](/variant/apc-p-arg653met), [APC p.Arg653Lys](/variant/apc-p-arg653lys), [APC p.Arg653Gly](/variant/apc-p-arg653gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related APC variant pages (same residue, condition, or type): [APC p.Arg653Gly](/variant/apc-p-arg653gly), [APC p.Arg653Lys](/variant/apc-p-arg653lys), [APC p.Arg653Met](/variant/apc-p-arg653met), [APC p.Arg653Thr](/variant/apc-p-arg653thr), [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), [APC c.1312+5G>C](/variant/apc-c-1312-plus-5g-c).

### 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 2026-10-14); 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 133524). 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.*