KANK4

Chr 1

KN motif and ankyrin repeat domains 4

Also known as: ANKRD38, dJ1078M7.1

NCBI Gene: 163782 ENSG00000132854 UniProt: Q5T7N3 OMIM: 614612

The protein regulates actin polymerization and cytoskeleton formation. Mutations cause autosomal recessive developmental delay, intellectual disability, and cerebellar atrophy with onset in infancy or early childhood. The gene shows moderate constraint against loss-of-function variants, with neurological manifestations being the primary clinical features.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to be involved in negative regulation of actin filament polymerization. Located in cytosol and microtubule cytoskeleton. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.80

Clinical Summary— KANK4

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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

245 VUS of 415 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?

0.80LOEUF

pLI 0.000

Z-score 2.51

OE 0.55 (0.39–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.20Z-score

OE missense 0.98 (0.91–1.05)

541 obs / 554.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.55 (0.39–0.80)

0≤0.351.4

Missense OE?0.98 (0.91–1.05)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 20 / 36.3Missense obs/exp: 541 / 554.4Syn Z: 0.79

This gene — mechanism propensity

0.6647th %ile

GOF

0.6443th %ile

LOF

0.3551th %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

415 submitted variants in ClinVar

ClinVar

Classification Summary

VUS245

Likely Benign95

Benign55

Conflicting8

245

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	11	231	3	0	245
Likely Benign	1	23	17	54	95
Benign	0	9	29	17	55
Conflicting	—				8
Total	12	263	49	71	403

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap KANK4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →