LIMK1

Chr 7

LIM domain kinase 1

Also known as: LIMK, LIMK-1

NCBI Gene: 3984 ENSG00000106683 UniProt: P53667 OMIM: 601329

LIMK1 encodes a serine/threonine kinase that regulates actin filament dynamics by phosphorylating and inactivating cofilin, thereby stabilizing the actin cytoskeleton and controlling cell motility, axonal outgrowth, and brain development. LIMK1 is highly constrained against loss-of-function variants and hemizygous deletions contribute to the visuospatial cognitive deficits seen in Williams syndrome. The gene plays a critical role in cytoskeletal regulation and neurodevelopmental processes.

OMIM ResearchSummary from RefSeq, UniProt

There are approximately 40 known eukaryotic LIM proteins, so named for the LIM domains they contain. LIM domains are highly conserved cysteine-rich structures containing 2 zinc fingers. Although zinc fingers usually function by binding to DNA or RNA, the LIM motif probably mediates protein-protein interactions. LIM kinase-1 and LIM kinase-2 belong to a small subfamily with a unique combination of 2 N-terminal LIM motifs and a C-terminal protein kinase domain. LIMK1 is a serine/threonine kinase that regulates actin polymerization via phosphorylation and inactivation of the actin binding factor cofilin. This protein is ubiquitously expressed during development and plays a role in many cellular processes associated with cytoskeletal structure. This protein also stimulates axon growth and may play a role in brain development. LIMK1 hemizygosity is implicated in the impaired visuospatial constructive cognition of Williams syndrome. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Feb 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.23

Clinical Summary— LIMK1

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 78 VUS of 155 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.23LOEUF

pLI 0.999

Z-score 4.97

OE 0.09 (0.04–0.23)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.63Z-score

OE missense 0.64 (0.58–0.71)

276 obs / 429.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.23)

0≤0.351.4

Missense OE?0.64 (0.58–0.71)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 3 / 34.5Missense obs/exp: 276 / 429.2Syn Z: -0.17

This gene — mechanism propensity

0.4289th %ile

GOF

0.6541th %ile

LOF

0.65top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). 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.

LOFprediction above median · LOEUF 0.23

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

155 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS78

Likely Benign40

Benign10

Conflicting1

Pathogenic

Likely Pathogenic

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	1	0	0	1
Likely Pathogenic	0	1	0	0	1
VUS	0	78	0	0	78
Likely Benign	0	3	6	31	40
Benign	0	3	4	3	10
Conflicting	—				1
Total	0	86	10	34	131

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

View in ClinVar →

169 pathogenic / likely-pathogenic (of 175) ClinVar copy-number / structural variants overlap LIMK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →