# NM_006231.4(POLE):c.2090C>G (p.Pro697Arg)

https://sugi.bio/variant/pole-p-pro697arg

## Summary

**POLE p.Pro697Arg (c.2090C>G)** is classified **Conflicting classifications of pathogenicity** in POLE (ClinVar, Conflicting submitters, 21 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.2473); Rare (popmax 0.175%, nfe); Associated with Hereditary cancer.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs36120395 · 21 submitters · 2 linked conditions · AlphaMissense likely benign · rare (popmax 0.175%, nfe)

## For patients & families {#patients}

This is a change in the POLE gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 21 submitters, and is linked to Hereditary cancer.

*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 | [POLE](https://sugi.bio/atlas/gene/POLE/) |
| Protein change (HGVS p.) | p.Pro697Arg |
| Coding change (HGVS c.) | c.2090C>G |
| MANE Select transcript | [NM_006231](https://www.ncbi.nlm.nih.gov/nuccore/NM_006231) |
| dbSNP | [rs36120395](https://www.ncbi.nlm.nih.gov/snp/rs36120395/) |
| Variant type | single nucleotide variant |
| Location | chr12:132668439-132668439 (GRCh38) |
| ClinVar | [VCV240423](https://www.ncbi.nlm.nih.gov/clinvar/variation/240423/) |

**All HGVS expressions:** `LRG_789:g.24086C>G`, `LRG_789t1:c.2090C>G`, `NC_000012.11:g.133245025G>C`, `NC_000012.12:g.132668439G>C`, `NG_033840.1:g.24086C>G`, `NM_006231.4:c.2090C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2473)
- REVEL 0.25 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -10.691 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP 9.852, GERP 0.824, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.2**. 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.*
- Regional missense constraint: **o/e 0.91** across the covering region of the MANE Select transcript (132,664,439–132,687,315), spanning 22,876 bp. Chi-square p 0.0025. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.175%** (nfe) · FAF95 0.169% · FAF99 0.166% · 2,063/1,179,306 in the highest group · 2,316/1,612,796 alleles overall — rare (popmax 0.175%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.187% | 534 |
| European (non-Finnish) (grpmax) | 0.175% | 572 |
| Admixed American | 0.117% | 854 |
| Finnish (not grpmax-eligible) | 0.05% | 2,001 |
| African / African-American | 0.036% | 2,777 |
| South Asian | 0.0077% | 12,983 |

Remaining individuals 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}

**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 **697** 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-06-01.

**Submitter consensus:** conflicting (12 Likely benign, 7 Uncertain significance, 2 Benign).

**Submission history:** 21 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2020-05-26 |
| Clinical Genetics, Academic Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-01-20 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-02-27 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-10-13 |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing | 2017-05-04 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | no assertion criteria provided | clinical testing |  |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely benign | criteria provided, single submitter | clinical testing | 2020-10-20 |
| Genetic Services Laboratory, University of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-22 |
| Sema4, Sema4 | Likely benign | criteria provided, single submitter | curation | 2021-07-03 |
| Mendelics | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-23 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-04 |
| Laboratorio de I+D, Fundación Centro Médico de Asturias | Benign | criteria provided, single submitter | clinical testing | 2025-07-13 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-18 |
| True Health Diagnostics | Uncertain significance | no assertion criteria provided | clinical testing | 2017-11-30 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-03-29 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-01-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-01 |

## Associated conditions {#conditions}

[Hereditary cancer](https://sugi.bio/atlas/disease/hereditary-cancer/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary cancer, not specified, Hereditary cancer-predisposing syndrome, not provided, Hereditary Cancer Syndrome, Tumor predisposition, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, AllHighlyPenetrant, none provided.

## Same-residue context {#hotspot}

Residue **697** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [POLE p.Pro697fs](/variant/pole-p-pro697fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related POLE variant pages (same residue, condition, or type): [POLE p.Pro697=](/variant/pole-p-pro697), [POLE p.Pro697Ser](/variant/pole-p-pro697ser), [POLE p.Pro697Ala](/variant/pole-p-pro697ala), [POLE p.Pro697His](/variant/pole-p-pro697his), [POLE p.Pro697Leu](/variant/pole-p-pro697leu), [POLE p.Pro697Thr](/variant/pole-p-pro697thr), [POLE c.1686+32C>G](/variant/pole-c-1686-plus-32c-g), [POLE p.Leu424Val](/variant/pole-p-leu424val).

### 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 240423). 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.*