KCTD1
Chr 18ADpotassium channel tetramerization domain containing 1
Also known as: C18orf5, DNRD, RMDA
The protein negatively regulates AP-2 transcription factors and the Wnt signaling pathway by enhancing ubiquitination and degradation of beta-catenin. Mutations cause scalp-ear-nipple syndrome and dental radicular dysplasia with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.86, LOEUF 0.44), indicating intolerance to protein-disrupting mutations.
Primary Disease Associations & Inheritance
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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.
Literature Evidence
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
269 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 10 | 39 | 0 | 49 |
Likely Pathogenic | 0 | 3 | 1 | 0 | 4 |
VUS | 1 | 138 | 15 | 1 | 155 |
Likely Benign | 0 | 4 | 7 | 21 | 32 |
Benign | 0 | 1 | 15 | 3 | 19 |
Conflicting | — | 5 | |||
| Total | 1 | 156 | 77 | 25 | 264 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
KCTD1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools