# NM_006502.3(POLH):c.1929G>A (p.Pro643=)

https://sugi.bio/variant/polh-p-pro643

## Summary

**POLH p.Pro643= (c.1929G>A)** is classified **Likely benign** in POLH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-13). Very rare (popmax 0.00668%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs375261104 · 1 submitter · very rare (popmax 0.00668%, afr)

## For patients & families {#patients}

This is a change in the POLH gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [POLH](https://sugi.bio/atlas/gene/POLH/) |
| Protein change (HGVS p.) | p.Pro643= |
| Coding change (HGVS c.) | c.1929G>A |
| MANE Select transcript | [NM_006502](https://www.ncbi.nlm.nih.gov/nuccore/NM_006502) |
| dbSNP | [rs375261104](https://www.ncbi.nlm.nih.gov/snp/rs375261104/) |
| Variant type | single nucleotide variant |
| Location | chr6:43614344-43614344 (GRCh38) |
| ClinVar | [VCV2896796](https://www.ncbi.nlm.nih.gov/clinvar/variation/2896796/) |

**All HGVS expressions:** `LRG_470:g.43204G>A`, `LRG_470t1:c.1929G>A`, `NC_000006.11:g.43582081G>A`, `NC_000006.12:g.43614344G>A`, `NG_009252.1:g.43204G>A`, `NG_028283.4:g.102257G>A`, `NM_001291969.2:c.1557G>A`, `NM_001291970.2:c.*613G>A`, `NM_006502.3:c.1929G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.30) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.073, GERP -3.45 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.234**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.30**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00668%** (afr) · FAF95 0.00255% · FAF99 0.00203% · 5/74,830 in the highest group · 47/1,609,432 alleles overall — very rare (popmax 0.00668%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00668% | 14,966 |
| East Asian | 0.00447% | 22,381 |
| European (non-Finnish) | 0.00315% | 31,791 |
| South Asian | 0.0022% | 45,489 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,226 |

*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}

**POLH** population constraint: LOEUF 0.846, pLI 3.0587e-09, missense-Z 1.5982. *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):

- **xeroderma pigmentosum variant type** — Definitive (AR)

## Protein context {#protein}

Residue **643** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 77.73, 62% of residues very-high.

**241 experimental structure(s)** (PDB): [2I5O](https://www.rcsb.org/structure/2I5O), [2LSK](https://www.rcsb.org/structure/2LSK), [3JAA](https://www.rcsb.org/structure/3JAA), [3MR2](https://www.rcsb.org/structure/3MR2), [3MR3](https://www.rcsb.org/structure/3MR3), [3MR5](https://www.rcsb.org/structure/3MR5) — incl. mutant structure 4YP3.

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

*Describes the biological roles of POLH (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:** POLH's established molecular role includes DNA-directed DNA polymerase activity.


### Pathways affected {#pathways}

POLH participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | curated |
| [Somatic hypermutation of immunoglobulin genes by error-prone mismatch repair (MMR)](https://reactome.org/content/detail/R-HSA-9968295) | curated |
| [Termination of translesion DNA synthesis](https://reactome.org/content/detail/R-HSA-5656169) | curated |
| [Translesion Synthesis by POLH](https://reactome.org/content/detail/R-HSA-110320) | curated |
| [Somatic hypermutation of immunoglobulin genes by error-prone base excision repair (BER)](https://reactome.org/content/detail/R-HSA-9968297) | electronic |

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

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

**Biological process:** DNA synthesis involved in DNA repair, response to UV-C, translesion synthesis.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-13.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-13 |

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

## Similar variants {#similar}

Related POLH variant pages (same residue, condition, or type): [POLH c.764+1G>A](/variant/polh-c-764-plus-1g-a), [POLH p.Arg167Ter](/variant/polh-p-arg167ter), [POLH p.Arg303Ter](/variant/polh-p-arg303ter), [POLH p.Arg356Ter](/variant/polh-p-arg356ter), [POLH p.Glu164Ter](/variant/polh-p-glu164ter), [POLH p.Ser213Ter](/variant/polh-p-ser213ter), [POLH p.Thr191Pro](/variant/polh-p-thr191pro), [POLH c.272+4A>G](/variant/polh-c-272-plus-4a-g).

### 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 2896796). 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.*