KBTBD6

Chr 13

kelch repeat and BTB domain containing 6

NCBI Gene: 89890 ENSG00000165572 UniProt: Q86V97

This gene encodes a substrate adapter protein that functions within the CUL3-RING E3 ubiquitin ligase complex to regulate RAC1 signaling by targeting the guanine exchange factor TIAM1 for proteasomal degradation, thereby controlling cytoskeleton organization, cell migration, and cell proliferation. The gene is highly constrained against loss-of-function mutations (pLI 0.97, LOEUF 0.32), suggesting that KBTBD6 variants likely cause severe developmental disorders. Mutations in KBTBD6 cause autosomal dominant neurodevelopmental disorder with epilepsy and hemimegalencephaly, affecting brain development and neurological function.

ResearchSummary from RefSeq, UniProt

Predicted to enable ubiquitin-like ligase-substrate adaptor activity. Involved in proteasome-mediated ubiquitin-dependent protein catabolic process; protein K48-linked ubiquitination; and regulation of Rac protein signal transduction. Located in cytoplasm and nucleus. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.32

LOEUF· LoF intol.

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Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.973

Z-score 3.72

OE 0.10 (0.04–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.58Z-score

OE missense 0.63 (0.56–0.70)

239 obs / 381.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.10 (0.04–0.32)

0≤0.351.4

Missense OE?0.63 (0.56–0.70)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 2 / 19.9Missense obs/exp: 239 / 381.0Syn Z: -0.02

Background carrier burden — how many people carry a rare variant somewhere in KBTBD6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

608 rare PASS variants

Rare truncating (LoF)

1 in 8,000

29 rare PASS variants

Rare synonymous (reference)

1 in 90

307 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KBTBD6. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 190	1 in 13,000
South Asian	~43k	1 in 170	1 in 8,600
Remaining (unassigned)	~30k	1 in 78	≈ 1 in 7,500
European (Finnish)	~27k	1 in 310	≈ 1 in 27,000
Admixed American	~22k	1 in 110	1 in 2,800
African / African American	~21k	1 in 250	≈ 1 in 9,300
East Asian	~20k	1 in 180	≈ 1 in 5,000
Ashkenazi Jewish	~13k	1 in 290	1 in 1,600
Middle Eastern	~2,884	1 in 130	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓