ZBTB46

Chr 20

zinc finger and BTB domain containing 46

Also known as: BTBD4, BZEL, RINZF, ZNF340, dJ583P15.7, dJ583P15.8

NCBI Gene: 140685 ENSG00000130584 UniProt: Q86UZ6 OMIM: 614639

ZBTB46 encodes a transcription repressor that regulates dendritic cell differentiation and immune tolerance to gut microbiota. The gene is highly constrained against loss-of-function variants (pLI 0.81, LOEUF 0.40), but no definitive Mendelian disease associations have been established in humans to date.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and transcription cis-regulatory region binding activity. Involved in regulation of transcription by RNA polymerase II. Predicted to be located in chromatin. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.40

Clinical Summary— ZBTB46

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.81) — some intolerance to loss-of-function variants.

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ClinVar Variants

93 VUS of 102 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.40LOEUF

pLI 0.809

Z-score 3.68

OE 0.17 (0.09–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.24Z-score

OE missense 0.69 (0.63–0.76)

287 obs / 415.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.17 (0.09–0.40)

0≤0.351.4

Missense OE?0.69 (0.63–0.76)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 4 / 23.0Missense obs/exp: 287 / 415.2Syn Z: -1.35

This gene — mechanism propensity

0.4686th %ile

GOF

0.3194th %ile

LOF

0.73top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.40

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

102 submitted variants in ClinVar

ClinVar

Classification Summary

VUS93

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	93	0	93
Likely Benign	1	1	2
Benign	0	0	0
Total	94	1	95

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

41 pathogenic / likely-pathogenic (of 57) ClinVar copy-number / structural variants overlap ZBTB46 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →