# NM_006231.4(POLE):c.6271C>T (p.Pro2091Ser)

https://sugi.bio/variant/pole-p-pro2091ser

## Summary

**POLE p.Pro2091Ser (c.6271C>T)** is classified **Conflicting classifications of pathogenicity** in POLE (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-06-05). AlphaMissense: ambiguous (0.4214); Ultra-rare (popmax 0.0593%, sas); Associated with colorectal cancer, susceptibility to, 12.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs572252265 · 6 submitters · 4 linked conditions · AlphaMissense ambiguous · ultra-rare (popmax 0.0593%, sas)

## 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 6 submitters, and is linked to colorectal cancer, susceptibility to, 12.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027855/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.Pro2091Ser |
| Coding change (HGVS c.) | c.6271C>T |
| MANE Select transcript | [NM_006231](https://www.ncbi.nlm.nih.gov/nuccore/NM_006231) |
| dbSNP | [rs572252265](https://www.ncbi.nlm.nih.gov/snp/rs572252265/) |
| Variant type | single nucleotide variant |
| Location | chr12:132632374-132632374 (GRCh38) |
| ClinVar | [VCV473789](https://www.ncbi.nlm.nih.gov/clinvar/variation/473789/) |

**All HGVS expressions:** `LRG_789:g.60151C>T`, `LRG_789t1:c.6271C>T`, `NC_000012.11:g.133208960G>A`, `NC_000012.12:g.132632374G>A`, `NG_033840.1:g.60151C>T`, `NM_006231.4:c.6271C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4214) — no call either way
- REVEL 0.451 (indeterminate)
- SaProt LLR -5.714 (tolerated)
- Conservation: phyloP 11.708, phastCons 1 — highly conserved
- CADD: **PHRED 22.7**. 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 0.92** across the covering region of the MANE Select transcript (132,624,700–132,661,015), spanning 36,315 bp. Chi-square p 0.001. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for POLE (2,847 scored positions, the nearest 2 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0593%** (sas) · FAF95 0.0466% · FAF99 0.0421% · 54/91,086 in the highest group · 60/1,614,042 alleles overall — ultra-rare (popmax 0.0593%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0593% | 1,687 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,621 |
| European (non-Finnish) | 0.000169% | 590,002 |

*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 **2091** 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 2025-06-05.

**Submitter consensus:** conflicting (5 Uncertain significance, 1 Likely benign).

**Submission history:** 6 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-19 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Likely benign | criteria provided, single submitter | clinical testing | 2017-12-27 |
| Neuberg Centre For Genomic Medicine, NCGM | Uncertain significance | criteria provided, single submitter | clinical testing |  |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-29 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-13 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-05 |

## Associated conditions {#conditions}

[colorectal cancer, susceptibility to, 12](https://sugi.bio/atlas/disease/colorectal-cancer-susceptibility-to-12/), [facial dysmorphism-immunodeficiency-livedo-short stature syndrome](https://sugi.bio/atlas/disease/facial-dysmorphism-immunodeficiency-livedo-short-stature-syndrome/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency](https://sugi.bio/atlas/disease/intrauterine-growth-retardation-metaphyseal-dysplasia-adrenal-hypoplasia-congenita-genital-anomalies-and-immunodeficiency/).

**Reported phenotype names (ClinVar):** Colorectal cancer, susceptibility to, 12, not provided, Facial dysmorphism-immunodeficiency-livedo-short stature syndrome, Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency, Hereditary cancer-predisposing syndrome, none provided, COLORECTAL CANCER, SUSCEPTIBILITY TO, ON CHROMOSOME 12q24, Facial dysmorphism, immunodeficiency, livedo, and short stature, FILS syndrome, IMAGEI SYNDROME.

## Similar variants {#similar}

Related POLE variant pages (same residue, condition, or type): [POLE p.Pro2091Ala](/variant/pole-p-pro2091ala), [POLE p.Pro2091Leu](/variant/pole-p-pro2091leu), [POLE p.Pro2091=](/variant/pole-p-pro2091), [POLE p.Pro2091Arg](/variant/pole-p-pro2091arg), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 473789). 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.*