# NM_000038.6(APC):c.570A>G (p.Glu190=)

https://sugi.bio/variant/apc-p-glu190

## Summary

**APC p.Glu190= (c.570A>G)** is classified **Benign** in APC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-23). Absent from gnomAD v4.1; Associated with familial adenomatous polyposis 1.

**At a glance:** Benign · review: Single submitter · rsID rs2149639628 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the APC gene that is classified as benign — not considered disease-causing, submitted by 1 submitter, 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.Glu190= |
| Coding change (HGVS c.) | c.570A>G |
| MANE Select transcript | [NM_000038](https://www.ncbi.nlm.nih.gov/nuccore/NM_000038) |
| dbSNP | [rs2149639628](https://www.ncbi.nlm.nih.gov/snp/rs2149639628/) |
| Variant type | single nucleotide variant |
| Location | chr5:112780828-112780828 (GRCh38) |
| ClinVar | [VCV3148047](https://www.ncbi.nlm.nih.gov/clinvar/variation/3148047/) |

**All HGVS expressions:** `LRG_130:g.93308A>G`, `LRG_130t1:c.570A>G`, `LRG_130t2:c.570A>G`, `LRG_130t3:c.570A>G`, `NC_000005.10:g.112780828A>G`, `NC_000005.9:g.112116525A>G`, `NG_008481.4:g.93308A>G`, `NM_000038.6:c.570A>G`, `NM_001127510.3:c.570A>G`, `NM_001127511.3:c.600A>G`, `NM_001354895.2:c.570A>G`, `NM_001354896.2:c.570A>G`, `NM_001354897.2:c.600A>G`, `NM_001354898.2:c.495A>G`, `NM_001354899.2:c.570A>G`, `NM_001354900.2:c.393A>G`, `NM_001354901.2:c.393A>G`, `NM_001354902.2:c.600A>G`, `NM_001354903.2:c.570A>G`, `NM_001354904.2:c.495A>G`, `NM_001354905.2:c.393A>G`, `NM_001354906.2:c.-466A>G`, `NM_001407446.1:c.600A>G`, `NM_001407447.1:c.570A>G`, `NM_001407448.1:c.570A>G`, `NM_001407449.1:c.570A>G`, `NM_001407450.1:c.570A>G`, `NM_001407451.1:c.495A>G`, `NM_001407452.1:c.570A>G`, `NM_001407453.1:c.393A>G`, `NM_001407454.1:c.570A>G`, `NM_001407455.1:c.570A>G`, `NM_001407456.1:c.570A>G`, `NM_001407457.1:c.570A>G`, `NM_001407458.1:c.570A>G`, `NM_001407459.1:c.570A>G`, `NM_001407460.1:c.570A>G`, `NM_001407467.1:c.570A>G`, `NM_001407469.1:c.570A>G`, `NM_001407470.1:c.-466A>G`, `NM_001407471.1:c.-466A>G`, `NM_001407472.1:c.-466A>G`, `NR_176365.1:n.740A>G`, `NR_176366.1:n.973A>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 2.677, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 7.691**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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 3/3, 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 **190** 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** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-23.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2024-02-23 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Familial adenomatous polyposis 1, POLYPOSIS, ADENOMATOUS INTESTINAL, FAMILIAL ADENOMATOUS POLYPOSIS 1, ATTENUATED.

## Similar variants {#similar}

Related APC variant pages (same residue, condition, or type): [APC p.Glu190Ala](/variant/apc-p-glu190ala), [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), [APC c.1409-3T>G](/variant/apc-c-1409-minus-3t-g), [APC c.1409-5A>G](/variant/apc-c-1409-minus-5a-g), [APC c.1626+2T>G](/variant/apc-c-1626-plus-2t-g).

### 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 3148047). 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.*