# NM_006231.4(POLE):c.1670C>G (p.Pro557Arg)

https://sugi.bio/variant/pole-p-pro557arg

## Summary

**POLE p.Pro557Arg (c.1670C>G)** is classified **Uncertain significance** in POLE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-26). AlphaMissense: likely pathogenic (0.5912); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2542133671 · 2 submitters · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the POLE gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters.

*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.Pro557Arg |
| Coding change (HGVS c.) | c.1670C>G |
| MANE Select transcript | [NM_006231](https://www.ncbi.nlm.nih.gov/nuccore/NM_006231) |
| dbSNP | [rs2542133671](https://www.ncbi.nlm.nih.gov/snp/rs2542133671/) |
| Variant type | single nucleotide variant |
| Location | chr12:132672643-132672643 (GRCh38) |
| ClinVar | [VCV2702674](https://www.ncbi.nlm.nih.gov/clinvar/variation/2702674/) |

**All HGVS expressions:** `LRG_789:g.19882C>G`, `LRG_789t1:c.1670C>G`, `NC_000012.11:g.133249229G>C`, `NC_000012.12:g.132672643G>C`, `NG_033840.1:g.19882C>G`, `NM_006231.4:c.1670C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.5912)
- REVEL 0.588 (indeterminate)
- SaProt LLR -9.061 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate
- Conservation: phyloP 11.837, GERP 1.85, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.8**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>A, Δ0.75 donor gain), 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: **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}

**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}


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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-08-26.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-13 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-26 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Same-residue context {#hotspot}

Residue **557** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [POLE p.Pro557fs](/variant/pole-p-pro557fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related POLE variant pages (same residue, condition, or type): [POLE p.Pro557Ser](/variant/pole-p-pro557ser), [POLE p.Pro557Ala](/variant/pole-p-pro557ala), [POLE p.Pro557fs](/variant/pole-p-pro557fs), [POLE c.1686+32C>G](/variant/pole-c-1686-plus-32c-g), [POLE c.3276-1G>C](/variant/pole-c-3276-minus-1g-c), [POLE c.5678+1G>T](/variant/pole-c-5678-plus-1g-t), [POLE p.Gln1763Ter](/variant/pole-p-gln1763ter), [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 2026-10-14); 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 2702674). 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.*