KCTD3

Chr 1

potassium channel tetramerization domain containing 3

Also known as: NY-REN-45

NCBI Gene: 51133 ENSG00000136636 UniProt: Q9Y597 OMIM: 613272

KCTD3 encodes an accessory subunit that regulates hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) by increasing its cell surface expression and current density. Mutations cause neuronal migration disorders and developmental delays with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variants, indicating that complete loss of KCTD3 function is likely pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the potassium channel tetramerization-domain containing (KCTD) protein family. Members of this protein family regulate the biophysical characteristics of ion channels. In mouse, this protein interacts with hyperpolarization-activated cyclic nucleotide-gated channel complex 3 and enhances its cell surface expression and current density. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

OMIM 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)

—

P/LP submissions

—

P/LP missense

0.41

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.101

Z-score 4.63

OE 0.25 (0.16–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.76Z-score

OE missense 0.62 (0.56–0.69)

263 obs / 422.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.25 (0.16–0.41)

0≤0.351.4

Missense OE?0.62 (0.56–0.69)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 11 / 44.2Missense obs/exp: 263 / 422.5Syn Z: 1.37

Background carrier burden — how many people carry a rare variant somewhere in KCTD3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

825 rare PASS variants

Rare truncating (LoF)

1 in 820

119 rare PASS variants

Rare synonymous (reference)

1 in 210

374 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KCTD3. 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 170	1 in 1,000
South Asian	~43k	1 in 110	1 in 790
Remaining (unassigned)	~30k	1 in 120	1 in 1,000
European (Finnish)	~27k	1 in 230	1 in 1,500
Admixed American	~22k	1 in 81	1 in 390
African / African American	~21k	1 in 110	1 in 540
East Asian	~20k	1 in 88	1 in 1,100
Ashkenazi Jewish	~13k	1 in 540	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 200	≈ 1 in 690

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): 8 of 18 coding exons well covered in gnomAD exomes; exons 1, 2, 3, 4, 5 and 5 more marginal. Genomes: all 18.? see exons ↓