# NM_006231.4(POLE):c.762G>A (p.Pro254=)

https://sugi.bio/variant/pole-p-pro254

## Summary

**POLE p.Pro254= (c.762G>A)** is classified **Benign/Likely benign** in POLE (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.0156%, eas); Associated with hereditary neoplastic syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs371334601 · 8 submitters · 2 linked conditions · ultra-rare (popmax 0.0156%, eas)

## 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 8 submitters, and is linked to hereditary neoplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/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.Pro254= |
| Coding change (HGVS c.) | c.762G>A |
| MANE Select transcript | [NM_006231](https://www.ncbi.nlm.nih.gov/nuccore/NM_006231) |
| dbSNP | [rs371334601](https://www.ncbi.nlm.nih.gov/snp/rs371334601/) |
| Variant type | single nucleotide variant |
| Location | chr12:132677402-132677402 (GRCh38) |
| ClinVar | [VCV391007](https://www.ncbi.nlm.nih.gov/clinvar/variation/391007/) |

**All HGVS expressions:** `LRG_789:g.15123G>A`, `LRG_789t1:c.762G>A`, `NC_000012.11:g.133253988C>T`, `NC_000012.12:g.132677402C>T`, `NG_033840.1:g.15123G>A`, `NM_006231.4:c.762G>A`

## 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 -12.429, GERP -3.07 — fast-evolving / accelerated position
- CADD: **PHRED 0.144**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.32 acceptor 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 (gnomAD v4.1): grpmax **0.0156%** (eas) · FAF95 0.00726% · FAF99 0.00514% · 7/44,892 in the highest group · 84/1,613,822 alleles overall — ultra-rare (popmax 0.0156%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0156% | 6,413 |
| European (non-Finnish) | 0.00576% | 17,352 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,827 |
| Finnish (not grpmax-eligible) | 0.00313% | 31,996 |
| South Asian | 0.0022% | 45,539 |
| Admixed American | 0.00167% | 59,986 |
| African / African-American | 0.00134% | 74,844 |

*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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-27.

**Submitter consensus:** conflicting (7 Likely benign, 1 Benign).

**Submission history:** 8 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-08-31 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-09-20 |
| Sema4, Sema4 | Likely benign | criteria provided, single submitter | curation | 2021-05-06 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2015-10-08 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Benign | criteria provided, single submitter | clinical testing | 2025-02-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-27 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-09-22 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [colorectal cancer, susceptibility to, 12](https://sugi.bio/atlas/disease/colorectal-cancer-susceptibility-to-12/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, not provided, POLE-related disorder, Colorectal cancer, susceptibility to, 12, not specified, Tumor predisposition, Neoplastic Syndromes, Hereditary, Hereditary neoplastic syndrome, Hereditary Cancer Syndrome, COLORECTAL CANCER, SUSCEPTIBILITY TO, ON CHROMOSOME 12q24.

## Similar variants {#similar}

Related POLE variant pages (same residue, condition, or type): [POLE p.Pro254Gln](/variant/pole-p-pro254gln), [POLE p.Pro254Leu](/variant/pole-p-pro254leu), [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), [POLE c.1106+4A>G](/variant/pole-c-1106-plus-4a-g).

### 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 391007). 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.*