Is TOP2B p.Ile227Ser (c.680T>G) pathogenic?

TOP2B p.Ile227Ser (c.680T>G) is classified Uncertain significance in TOP2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-09). AlphaMissense: likely pathogenic (0.8425); Absent from gnomAD v4.1; Associated with B-cell immunodeficiency, distal limb anomalies, and urogenital malformations.

What condition is associated with TOP2B p.Ile227Ser (c.680T>G)?

TOP2B p.Ile227Ser (c.680T>G) is associated with B-cell immunodeficiency, distal limb anomalies, and urogenital malformations (ClinVar).

How common is TOP2B p.Ile227Ser (c.680T>G) in the general population?

TOP2B p.Ile227Ser (c.680T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TOP2B p.Ile227Ser (c.680T>G)?

AlphaMissense predicts likely pathogenic (score 0.8425) — an in-silico prediction, not a clinical call.

TOP2B p.Ile227Ser

Q: How is B-cell immunodeficiency-limb anomaly-urogenital malformation syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.680T>G · rs2470366708 · VCV2099753

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8425 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

B-cell immunodeficiency, distal limb anomalies, and urogenital malformations

Computational evidence

Protein change
AlphaMissense	0.8425	likely pathogenic
REVEL	0.498	indeterminate
SaProt	LLR -12.94	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 7,273 bp · p 1.4e-06 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TOP2B
Protein: p.Ile227Ser
Coding: c.680T>G
MANE Select: NM_001330700
dbSNP: rs2470366708
Type: single nucleotide variant
Location: chr3:25636108 (GRCh38)
Gene constraint: LOEUF 0.328 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.09 · 21 PDB
Residue 227: a β-strand

Full TOP2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

B-cell immunodeficiency, distal limb anomalies, and urogenital malformations — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For B-cell immunodeficiency-limb anomaly-urogenital malformation syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Antenatal

Similar variants

TOP2B p.Glu547Gln Uncertain significance ★★ ⚠ same condition
TOP2B p.Ile623Thr Uncertain significance ★★ ⚠ same condition
TOP2B p.Ile789Thr Uncertain significance ★★ ⚠ same condition
TOP2B p.Thr1317Ile Uncertain significance ★★ ⚠ same condition
TOP2B p.Val955Leu Uncertain significance ★★ ⚠ same condition
TOP2B p.Pro1572Leu Benign/Likely benign ★★ same condition
TOP2B p.Ala490Pro Pathogenic ★ same condition
TOP2B p.Asp1384Ala Uncertain significance ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/top2b-p-ile227ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown