KBTBD8

Chr 3

kelch repeat and BTB domain containing 8

Also known as: TA-KRP, TAKRP

NCBI Gene: 84541 ENSG00000163376 UniProt: Q8NFY9 OMIM: 616607

KBTBD8 encodes a substrate-specific adapter protein that forms part of an E3 ubiquitin ligase complex and regulates neural crest specification by modulating ribosomal processing through monoubiquitination of NOLC1 and TCOF1. Mutations cause autosomal recessive developmental delay with dysmorphic facies and dental anomalies, reflecting the protein's critical role in neural crest development. The gene shows tolerance to loss-of-function variants (pLI near 0), consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable ubiquitin-like ligase-substrate adaptor activity. Involved in neural crest cell development; neural crest formation; and protein monoubiquitination. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.82

Clinical Summary— KBTBD8

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

67 VUS of 68 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.82LOEUF

pLI 0.000

Z-score 2.21

OE 0.51 (0.33–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.25Z-score

OE missense 0.80 (0.72–0.89)

258 obs / 321.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.51 (0.33–0.82)

0≤0.351.4

Missense OE?0.80 (0.72–0.89)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 12 / 23.6Missense obs/exp: 258 / 321.3Syn Z: 0.30

This gene — mechanism propensity

0.6453th %ile

GOF

0.6639th %ile

LOF

0.3065th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

68 submitted variants in ClinVar

ClinVar

Classification Summary

VUS67

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	67	67
Likely Benign	0	0
Benign	0	0
Total	67	67

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap KBTBD8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →