KCTD5

Chr 16

potassium channel tetramerization domain containing 5

NCBI Gene: 54442 ENSG00000167977 OMIM: 611285

KCTD5 encodes a protein that functions as a substrate adapter in E3 ubiquitin ligase complexes, facilitating targeted protein degradation through the ubiquitin-proteasome system. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, refractory seizures, and progressive neurodegeneration. The gene shows moderate tolerance to loss-of-function variants (LOEUF 0.789), consistent with the recessive inheritance pattern observed in affected patients.

OMIM ResearchSummary from RefSeq, UniProt

Enables identical protein binding activity. Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Located in cytosol. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.79

Clinical Summary— KCTD5

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

27 VUS of 39 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?

0.79LOEUF

pLI 0.054

Z-score 2.07

OE 0.34 (0.17–0.79)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.19Z-score

OE missense 0.69 (0.58–0.83)

83 obs / 119.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.17–0.79)

0≤0.351.4

Missense OE?0.69 (0.58–0.83)

0≤0.61.4

Synonymous OE?1.46

0≤1.21.6

LoF obs/exp: 4 / 11.6Missense obs/exp: 83 / 119.7Syn Z: -2.69

This gene — mechanism propensity

0.7131th %ile

GOF

0.6540th %ile

LOF

0.3940th %ile

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

DNprediction above median

GOFprediction 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

39 submitted variants in ClinVar

ClinVar

Classification Summary

VUS27

Likely Benign1

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	27	0	27
Likely Benign	0	1	1
Benign	0	0	0
Total	27	1	28

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

View in ClinVar →

32 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap KCTD5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →