# NM_199420.4(POLQ):c.543C>T (p.Phe181=)

https://sugi.bio/variant/polq-p-phe181

## Summary

**POLQ p.Phe181= (c.543C>T)** is classified **Benign** in POLQ (ClinVar, Single submitter, 2 submitters; last evaluated 2026-08-07). Common (popmax 7.23%, mid) — too common for a highly-penetrant pathogenic allele; Associated with hereditary breast carcinoma.

**At a glance:** Benign · review: Single submitter · rsID rs36065146 · 2 submitters · 1 linked condition · common (popmax 7.23%, mid) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the POLQ gene that is classified as benign — not considered disease-causing, submitted by 2 submitters, and is linked to hereditary breast carcinoma.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Multigenic/multifactorial |
| Age of onset (of this condition) | Adult, Elderly |
| Clinical trials | 10 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017142/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [POLQ](https://sugi.bio/atlas/gene/POLQ/) |
| Protein change (HGVS p.) | p.Phe181= |
| Coding change (HGVS c.) | c.543C>T |
| MANE Select transcript | [NM_199420](https://www.ncbi.nlm.nih.gov/nuccore/NM_199420) |
| dbSNP | [rs36065146](https://www.ncbi.nlm.nih.gov/snp/rs36065146/) |
| Variant type | single nucleotide variant |
| Location | chr3:121539521-121539521 (GRCh38) |
| ClinVar | [VCV3056272](https://www.ncbi.nlm.nih.gov/clinvar/variation/3056272/) |

**All HGVS expressions:** `NC_000003.11:g.121258368G>A`, `NC_000003.12:g.121539521G>A`, `NM_199420.4:c.543C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 7.23%, mid) — too common for a highly-penetrant pathogenic allele.

- **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 0.487, GERP -2.73, phastCons 0.979 — weakly conserved position
- CADD: **PHRED 6.996**. 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 **7.23%** (mid) · FAF95 6.67% · FAF99 6.45% · 438/6,060 in the highest group · 77,752/1,612,262 alleles overall — common (popmax 7.23%, mid) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 10.5% | 10 |
| Middle Eastern (grpmax) | 7.23% | 14 |
| European (non-Finnish) | 5.27% | 19 |
| Remaining individuals (not grpmax-eligible) | 5.22% | 19 |
| South Asian | 4.94% | 20 |
| Admixed American | 3.77% | 26 |
| Finnish (not grpmax-eligible) | 2.24% | 45 |
| African / African-American | 0.872% | 115 |
| Amish (not grpmax-eligible) | 0.219% | 456 |
| East Asian | 0.0869% | 1,150 |

Ashkenazi Jewish 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.*

## Protein context {#protein}

Residue **181** lies in the umuc domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 70.62, 49% of residues very-high.

**19 experimental structure(s)** (PDB): [1T94](https://www.rcsb.org/structure/1T94), [2LSI](https://www.rcsb.org/structure/2LSI), [2OH2](https://www.rcsb.org/structure/2OH2), [2W7O](https://www.rcsb.org/structure/2W7O), [2W7P](https://www.rcsb.org/structure/2W7P), [3IN5](https://www.rcsb.org/structure/3IN5).

## What this gene does {#gene-function}

*Describes the biological roles of POLQ (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:** POLQ's established molecular role includes DNA-directed DNA polymerase activity. p.Phe181= falls in the umuc domain.


### Pathways affected {#pathways}

POLQ participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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 |
| [Termination of translesion DNA synthesis](https://reactome.org/content/detail/R-HSA-5656169) | curated |
| [Translesion synthesis by POLK](https://reactome.org/content/detail/R-HSA-5655862) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** DNA-directed DNA polymerase activity.

**Biological process:** DNA repair, nucleotide-excision repair, DNA gap filling, DNA damage response, translesion synthesis, cellular response to UV, error-prone translesion synthesis.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-08-07.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-07-10 |
| Genomic Medicine Laboratory, Hospital de Clinicas de Porto Alegre | Benign | criteria provided, single submitter | research | 2026-08-07 |

## Associated conditions {#conditions}

[hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/).

**Reported phenotype names (ClinVar):** Familial cancer of breast, POLQ-related disorder, POLQ-related condition, hereditary breast carcinoma, BREAST CANCER, FAMILIAL, Hereditary breast cancer.

## Similar variants {#similar}

Related POLQ variant pages (same residue, condition, or type): [POLQ p.Phe181Leu](/variant/polq-p-phe181leu), [POLQ p.Ala2464Thr](/variant/polq-p-ala2464thr), [POLQ p.Asn1339=](/variant/polq-p-asn1339), [POLQ p.Gly479=](/variant/polq-p-gly479), [POLQ p.Ala1150Pro](/variant/polq-p-ala1150pro), [POLQ c.1816+53T>G](/variant/polq-c-1816-plus-53t-g), [POLQ c.1959+8C>G](/variant/polq-c-1959-plus-8c-g), [POLQ c.2153+27C>T](/variant/polq-c-2153-plus-27c-t).

### 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 3056272). 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.*