# NM_001330700.2(TOP2B):c.1468G>C (p.Ala490Pro)

https://sugi.bio/variant/top2b-p-ala490pro

## Summary

**TOP2B p.Ala490Pro (c.1468G>C)** is classified **Pathogenic** in TOP2B (ClinVar, Single submitter, 2 submitters; last evaluated 2023-11-24). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1; Associated with TOP2B-related disorder.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2125377898 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the TOP2B gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to TOP2B-related disorder.

*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 | [TOP2B](https://sugi.bio/atlas/gene/TOP2B/) |
| Protein change (HGVS p.) | p.Ala490Pro |
| Coding change (HGVS c.) | c.1468G>C |
| MANE Select transcript | [NM_001330700](https://www.ncbi.nlm.nih.gov/nuccore/NM_001330700) |
| dbSNP | [rs2125377898](https://www.ncbi.nlm.nih.gov/snp/rs2125377898/) |
| Variant type | single nucleotide variant |
| Location | chr3:25630407-25630407 (GRCh38) |
| ClinVar | [VCV1319985](https://www.ncbi.nlm.nih.gov/clinvar/variation/1319985/) |

**All HGVS expressions:** `NC_000003.11:g.25671898C>G`, `NC_000003.12:g.25630407C>G`, `NG_052961.1:g.38966G>C`, `NM_001068.3:c.1453G>C`, `NM_001330700.2:c.1468G>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9994) — concordant with the pathogenic call
- REVEL 0.694 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.963 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.738, GERP 2.19, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in TOP2B (of 9,621 modeled).
- CADD: **PHRED 26.9**. 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 0.43** across the covering region of the MANE Select transcript (25,630,039–25,630,915), spanning 876 bp. Chi-square p 1.8e-12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.46 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**TOP2B** population constraint: LOEUF 0.328, pLI 1, missense-Z 3.7013. *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):

- **B-cell immunodeficiency, distal limb anomalies, and urogenital malformations** — Moderate (AD)

## Protein context {#protein}

Residue **490** lies in a UniProt-annotated variant site (in bilu; decreased protein abundance; severely decreased dna topoisomerase type ii (double strand cut, atp-hydrolyzing) activity); an α-helix; the toprim domain.

AlphaFold model confidence (whole protein): pLDDT 74.09, 45% of residues very-high.

**21 experimental structure(s)** (PDB): [25EC](https://www.rcsb.org/structure/25EC), [3QX3](https://www.rcsb.org/structure/3QX3), [4G0U](https://www.rcsb.org/structure/4G0U), [4G0V](https://www.rcsb.org/structure/4G0V), [4G0W](https://www.rcsb.org/structure/4G0W), [4J3N](https://www.rcsb.org/structure/4J3N).

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

*Describes the biological roles of TOP2B (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:** TOP2B's established molecular role includes chromatin binding. p.Ala490Pro falls in the toprim domain.


### Pathways affected {#pathways}

TOP2B participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [SUMOylation of DNA replication proteins](https://reactome.org/content/detail/R-HSA-4615885) | curated |

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

**Molecular function:** chromatin binding, DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity.

**Biological process:** DNA topological change, B cell differentiation, positive regulation of single stranded viral RNA replication via double stranded DNA intermediate.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-24.

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

**Submission history:** 2 submissions (2021–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2021-11-04 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-24 |

## Associated conditions {#conditions}

[TOP2B-related disorder](https://sugi.bio/atlas/disease/top2b-related-disorder/), [B-cell immunodeficiency, distal limb anomalies, and urogenital malformations](https://sugi.bio/atlas/disease/b-cell-immunodeficiency-distal-limb-anomalies-and-urogenital-malformations/).

**Reported phenotype names (ClinVar):** TOP2B-related disorder, B-cell immunodeficiency, distal limb anomalies, and urogenital malformations, TOP2B-related condition, HOFFMAN SYNDROME, BILU SYNDROME.

## Similar variants {#similar}

Related TOP2B variant pages (same residue, condition, or type): [TOP2B p.Ala490=](/variant/top2b-p-ala490), [TOP2B p.Glu547Gln](/variant/top2b-p-glu547gln), [TOP2B p.Ile227Ser](/variant/top2b-p-ile227ser), [TOP2B p.Ile623Thr](/variant/top2b-p-ile623thr), [TOP2B p.Ile789Thr](/variant/top2b-p-ile789thr), [TOP2B p.Met1624Val](/variant/top2b-p-met1624val), [TOP2B p.Thr1317Ile](/variant/top2b-p-thr1317ile), [TOP2B p.Val1504Phe](/variant/top2b-p-val1504phe).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 1319985). 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.*