KCNF1

Chr 2

potassium voltage-gated channel modifier subfamily F member 1

Also known as: IK8, KCNF, KV5.1, kH1

NCBI Gene: 3754 ENSG00000162975 UniProt: Q9H3M0 OMIM: 603787

The protein functions as a regulatory alpha-subunit of voltage-gated potassium channels that modulates the expression and gating kinetics of KCNB1 and KCNB2 channels by affecting deactivation and inactivation processes. Mutations in KCNF1 cause early infantile epileptic encephalopathy, an autosomal recessive disorder characterized by seizure onset in the first months of life. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.66), and the severe early-onset neurological phenotype reflects the critical role of potassium channel regulation in neuronal excitability.

OMIM ResearchSummary from RefSeq, UniProt

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily F. This gene is intronless and expressed in all tissues tested, including the heart, skeletal muscle, brain, kidney, and pancreas. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.66

Clinical Summary— KCNF1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 47 VUS of 51 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.66LOEUF

pLI 0.246

Z-score 2.37

OE 0.25 (0.12–0.66)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

3.38Z-score

OE missense 0.48 (0.42–0.55)

160 obs / 333.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.25 (0.12–0.66)

0≤0.351.4

Missense OE?0.48 (0.42–0.55)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 3 / 11.8Missense obs/exp: 160 / 333.8Syn Z: 0.98

This gene — mechanism propensity

0.75top 25%

GOF

0.86top 5%

LOF

0.2386th %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

51 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS47

Likely Benign1

Benign2

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	1	0	1
VUS	47	0	47
Likely Benign	1	0	1
Benign	0	2	2
Total	49	2	51

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

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19 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap KCNF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →