ACTL6A

Chr 3

actin like 6A

Also known as: ACTL6, ARPN-BETA, Arp4, BAF53A, INO80K, SMARCN1

NCBI Gene: 86 ENSG00000136518 UniProt: O96019 OMIM: 604958

This gene encodes ACTL6A, a 53 kDa subunit of the BAF chromatin remodeling complex that is essential for transcriptional regulation during neural development, specifically required for neural progenitor proliferation and the transition to postmitotic neurons. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability, developmental delay, and epilepsy, typically presenting in early childhood. The gene is highly constrained against loss-of-function variants (pLI 0.997), indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a family member of actin-related proteins (ARPs), which share significant amino acid sequence identity to conventional actins. Both actins and ARPs have an actin fold, which is an ATP-binding cleft, as a common feature. The ARPs are involved in diverse cellular processes, including vesicular transport, spindle orientation, nuclear migration and chromatin remodeling. This gene encodes a 53 kDa subunit protein of the BAF (BRG1/brm-associated factor) complex in mammals, which is functionally related to SWI/SNF complex in S. cerevisiae and Drosophila; the latter is thought to facilitate transcriptional activation of specific genes by antagonizing chromatin-mediated transcriptional repression. Together with beta-actin, it is required for maximal ATPase activity of BRG1, and for the association of the BAF complex with chromatin/matrix. Three transcript variants that encode two different protein isoforms have been described. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.25

Clinical Summary— ACTL6A

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Gene-Disease Validity (ClinGen)

ACTL6A-related BAFopathy · ADModerate

Moderate evidence — consider for supplementary testing

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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.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.25LOEUF

pLI 0.997

Z-score 4.32

OE 0.08 (0.03–0.25)

Highly constrained

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

Missense Constraint?

2.94Z-score

OE missense 0.46 (0.40–0.54)

110 obs / 237.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.25)

0≤0.351.4

Missense OE?0.46 (0.40–0.54)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 2 / 25.6Missense obs/exp: 110 / 237.5Syn Z: 0.28

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateACTL6A-related BAFopathy (developmental disorder with or without cardiac and limb anomalies)LOFAD

This gene — mechanism propensity

0.4090th %ile

GOF

0.4579th %ile

LOF

0.71top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.25

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.