# NM_006231.4(POLE):c.6495C>T (p.Arg2165=)

https://sugi.bio/variant/pole-p-arg2165

## Summary

**POLE p.Arg2165= (c.6495C>T)** is classified **Benign/Likely benign** in POLE (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.0802%, nfe); Associated with intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs114778730 · 13 submitters · 5 linked conditions · ultra-rare (popmax 0.0802%, 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 13 submitters, and is linked to intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency.

*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/0025721/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.Arg2165= |
| Coding change (HGVS c.) | c.6495C>T |
| MANE Select transcript | [NM_006231](https://www.ncbi.nlm.nih.gov/nuccore/NM_006231) |
| dbSNP | [rs114778730](https://www.ncbi.nlm.nih.gov/snp/rs114778730/) |
| Variant type | single nucleotide variant |
| Location | chr12:132626153-132626153 (GRCh38) |
| ClinVar | [VCV240598](https://www.ncbi.nlm.nih.gov/clinvar/variation/240598/) |

**All HGVS expressions:** `LRG_789:g.66372C>T`, `LRG_789t1:c.6495C>T`, `NC_000012.11:g.133202739G>A`, `NC_000012.12:g.132626153G>A`, `NG_033840.1:g.66372C>T`, `NM_006231.4:c.6495C>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 -2.094 — fast-evolving / accelerated position
- CADD: **PHRED 3.671**. 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 **0.0802%** (nfe) · FAF95 0.0759% · FAF99 0.0743% · 945/1,177,976 in the highest group · 1,096/1,609,544 alleles overall — ultra-rare (popmax 0.0802%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0991% | 1,009 |
| European (non-Finnish) (grpmax) | 0.0802% | 1,247 |
| Remaining individuals (not grpmax-eligible) | 0.0642% | 1,558 |
| Admixed American | 0.0607% | 1,648 |
| African / African-American | 0.012% | 8,324 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00339% | 29,514 |
| South Asian | 0.00221% | 45,210 |

Finnish 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 **2165** lies in a β-strand; a UniProt-annotated variant site (in imagei); a UniProt-annotated variant site (in).

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 (10 Likely benign, 3 Benign).

**Submission history:** 13 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Benign | criteria provided, single submitter | clinical testing | 2018-06-26 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2015-06-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-27 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-01 |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-25 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely benign | no assertion criteria provided | clinical testing |  |
| Sema4, Sema4 | Likely benign | criteria provided, single submitter | curation | 2021-02-10 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2022-05-12 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely benign | criteria provided, single submitter | clinical testing | 2023-11-29 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-04 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-22 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-05-27 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-10-14 |

## Associated conditions {#conditions}

[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/), [colon carcinoma](https://sugi.bio/atlas/disease/colon-carcinoma/), [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/).

**Reported phenotype names (ClinVar):** Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency, not provided, Hereditary cancer-predisposing syndrome, Carcinoma of colon, not specified, Colorectal cancer, susceptibility to, 12, Facial dysmorphism-immunodeficiency-livedo-short stature syndrome, IMAGEI SYNDROME, Facial dysmorphism, immunodeficiency, livedo, and short stature, FILS syndrome.

## Similar variants {#similar}

Related POLE variant pages (same residue, condition, or type): [POLE p.Arg2165Cys](/variant/pole-p-arg2165cys), [POLE p.Arg2165His](/variant/pole-p-arg2165his), [POLE p.Arg2165Gly](/variant/pole-p-arg2165gly), [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 240598). 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.*