# NM_006231.4(POLE):c.6675C>T (p.Arg2225=)

https://sugi.bio/variant/pole-p-arg2225

## Summary

**POLE p.Arg2225= (c.6675C>T)** is classified **Benign/Likely benign** in POLE (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-02-04). Rare (popmax 0.261%, nfe); Associated with familial colorectal cancer type X.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs149973644 · 20 submitters · 4 linked conditions · rare (popmax 0.261%, nfe)

## For patients & families {#patients}

This is a change in the POLE gene that is classified as benign/likely benign — not considered disease-causing, submitted by 20 submitters, and is linked to familial colorectal cancer type X.

*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 |
| Age of onset (of this condition) | Adult, Elderly |
| Diagnostic panels | POLE is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Familial colorectal cancer Type X** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Weight loss — Very frequent (99-80%)
- Constipation — Very frequent (99-80%)
- Malabsorption — Very frequent (99-80%)
- Abdominal pain — Very frequent (99-80%)
- Glioblastoma multiforme — Very frequent (99-80%)
- Fatigue — Very frequent (99-80%)
- Atypical behavior — Frequent (79-30%)
- Depression — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0021840/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [POLE](https://sugi.bio/atlas/gene/POLE/) |
| Protein change (HGVS p.) | p.Arg2225= |
| Coding change (HGVS c.) | c.6675C>T |
| MANE Select transcript | [NM_006231](https://www.ncbi.nlm.nih.gov/nuccore/NM_006231) |
| dbSNP | [rs149973644](https://www.ncbi.nlm.nih.gov/snp/rs149973644/) |
| Variant type | single nucleotide variant |
| Location | chr12:132624977-132624977 (GRCh38) |
| ClinVar | [VCV220842](https://www.ncbi.nlm.nih.gov/clinvar/variation/220842/) |

**All HGVS expressions:** `LRG_789:g.67548C>T`, `LRG_789t1:c.6675C>T`, `NC_000012.11:g.133201563G>A`, `NC_000012.12:g.132624977G>A`, `NG_033840.1:g.67548C>T`, `NM_006231.4:c.6675C>T`

## 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 -3.402 — fast-evolving / accelerated position
- CADD: **PHRED 2.138**. 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 (gnomAD v4.1): grpmax **0.261%** (nfe) · FAF95 0.254% · FAF99 0.25% · 3,084/1,179,886 in the highest group · 3,387/1,613,792 alleles overall — rare (popmax 0.261%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.261% | 383 |
| Remaining individuals (not grpmax-eligible) | 0.235% | 425 |
| South Asian | 0.0813% | 1,231 |
| Middle Eastern | 0.066% | 1,515 |
| Admixed American | 0.0433% | 2,308 |
| African / African-American | 0.04% | 2,502 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0236% | 4,229 |
| Finnish (not grpmax-eligible) | 0.0219% | 4,558 |
| East Asian | 0.00223% | 44,882 |

*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}

**POLE** population constraint: LOEUF 0.75, pLI 2.7396e-38, missense-Z 2.6706; ClinGen dosage — haploinsufficiency 1/3, 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):

- **POLE-related polyposis and colorectal cancer syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **2225** lies in a UniProt-annotated variant site (in imagei).

AlphaFold model confidence (whole protein): pLDDT 80.32, 31% of residues very-high.

**18 experimental structure(s)** (PDB): [5VBN](https://www.rcsb.org/structure/5VBN), [7PFO](https://www.rcsb.org/structure/7PFO), [7PLO](https://www.rcsb.org/structure/7PLO), [9B8S](https://www.rcsb.org/structure/9B8S), [9B8T](https://www.rcsb.org/structure/9B8T), [9F6D](https://www.rcsb.org/structure/9F6D).

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

*Describes the biological roles of POLE (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:** POLE's established molecular role includes DNA binding.


### Pathways affected {#pathways}

POLE participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of the pre-replicative complex](https://reactome.org/content/detail/R-HSA-68962) | curated |
| [DNA replication initiation](https://reactome.org/content/detail/R-HSA-68952) | curated |
| [Dual Incision in GG-NER](https://reactome.org/content/detail/R-HSA-5696400) | curated |
| [Dual incision in TC-NER](https://reactome.org/content/detail/R-HSA-6782135) | curated |
| [Gap-filling DNA repair synthesis and ligation in GG-NER](https://reactome.org/content/detail/R-HSA-5696397) | curated |
| [Gap-filling DNA repair synthesis and ligation in TC-NER](https://reactome.org/content/detail/R-HSA-6782210) | curated |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | curated |
| [PCNA-Dependent Long Patch Base Excision Repair](https://reactome.org/content/detail/R-HSA-5651801) | curated |
| [Recognition of DNA damage by PCNA-containing replication complex](https://reactome.org/content/detail/R-HSA-110314) | curated |
| [Termination of translesion DNA synthesis](https://reactome.org/content/detail/R-HSA-5656169) | curated |

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

**Molecular function:** DNA binding, chromatin binding, DNA-directed DNA polymerase activity.

**Biological process:** G1/S transition of mitotic cell cycle, DNA synthesis involved in DNA repair, DNA replication, DNA-templated DNA replication, base-excision repair, gap-filling, nucleotide-excision repair, DNA gap filling.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (14 Likely benign, 6 Benign).

**Submission history:** 20 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing | 2017-05-09 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Likely benign | no assertion criteria provided | clinical testing |  |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2021-11-22 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2022-05-05 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely benign | criteria provided, single submitter | clinical testing | 2023-03-24 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2015-06-19 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely benign | criteria provided, single submitter | clinical testing | 2023-04-06 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-07-27 |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Sema4, Sema4 | Benign | criteria provided, single submitter | curation | 2020-09-16 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Benign | criteria provided, single submitter | clinical testing | 2017-06-09 |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Benign | criteria provided, single submitter | clinical testing | 2023-07-07 |
| 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 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-21 |

## Associated conditions {#conditions}

[familial colorectal cancer type X](https://sugi.bio/atlas/disease/familial-colorectal-cancer-type-x/), [colorectal cancer, susceptibility to, 12](https://sugi.bio/atlas/disease/colorectal-cancer-susceptibility-to-12/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [Polymerase proofreading-related adenomatous polyposis](https://sugi.bio/atlas/disease/polymerase-proofreading-related-adenomatous-polyposis/).

**Reported phenotype names (ClinVar):** Familial colorectal cancer type X, not specified, Hereditary cancer-predisposing syndrome, not provided, Colorectal cancer, susceptibility to, 12, Polymerase proofreading-related adenomatous polyposis, Polymerase proofreading associated polyposis, Polymerase proofreading–associated polyposis (PPAP), Hereditary Cancer Syndrome, Tumor predisposition.

## Similar variants {#similar}

Related POLE variant pages (same residue, condition, or type): [POLE p.Arg2225Cys](/variant/pole-p-arg2225cys), [POLE p.Arg2225Gly](/variant/pole-p-arg2225gly), [POLE p.Arg2225His](/variant/pole-p-arg2225his), [POLE c.1686+32C>G](/variant/pole-c-1686-plus-32c-g), [POLE c.5678+1G>T](/variant/pole-c-5678-plus-1g-t), [POLE p.Leu424Val](/variant/pole-p-leu424val), [POLE c.1020+5G>A](/variant/pole-c-1020-plus-5g-a), [POLE c.1106+3G>C](/variant/pole-c-1106-plus-3g-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 220842). 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.*