ACTL6A-related BAFopathy

Summary

ACTL6A-related BAFopathy (MONDO:0700121) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ACTL6A-related BAFopathy
Mondo ID	MONDO:0700121
Is cancer (heuristic)	no

Data availability: 3 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › BAFopathy › ACTL6A-related BAFopathy

Related subtypes (14): Coffin-Siris syndrome 1, Baraitser-Winter syndrome 1, intellectual disability-sparse hair-brachydactyly syndrome, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, Coffin-Siris syndrome 5, Dias-Logan syndrome, Coffin-Siris syndrome 8, intellectual developmental disorder with severe speech and ambulation defects, Coffin-Siris syndrome 6, intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities, PBRM1-related BAFopathy, SMARCC1-associated developmental dysgenesis syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
549661	NM_004301.5(ACTL6A):c.1129C>T (p.Arg377Trp)	ACTL6A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1177318	NM_004301.5(ACTL6A):c.377C>T (p.Pro126Leu)	ACTL6A	Uncertain significance	criteria provided, single submitter
1177319	NM_004301.5(ACTL6A):c.1165C>T (p.Arg389Trp)	ACTL6A	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTL6A	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACTL6A	HGNC:24124	ENSG00000136518	O96019	Actin-like protein 6A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACTL6A	Actin-like protein 6A	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACTL6A	Other/Unknown	no		Actin, Actin_CS, ATPase_NBD

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
ganglionic eminence	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTL6A	272	ubiquitous	marker	primordial germ cell in gonad, calcaneal tendon, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTL6A	5,583

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTL6A	O96019	25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the non-canonical BAF (ncBAF) complex	1	671.8×	0.010	ACTL6A
Formation of the canonical BAF (cBAF) complex	1	634.4×	0.010	ACTL6A
Formation of the polybromo-BAF (pBAF) complex	1	634.4×	0.010	ACTL6A
Formation of the embryonic stem cell BAF (esBAF) complex	1	601.0×	0.010	ACTL6A
Global Genome Nucleotide Excision Repair (GG-NER)	1	456.8×	0.010	ACTL6A
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	456.8×	0.010	ACTL6A
Regulation of endogenous retroelements	1	368.4×	0.010	ACTL6A
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	300.5×	0.010	ACTL6A
DNA Damage Recognition in GG-NER	1	285.5×	0.010	ACTL6A
Nucleotide Excision Repair	1	285.5×	0.010	ACTL6A
Regulation of MITF-M-dependent genes involved in pigmentation	1	265.6×	0.010	ACTL6A
MITF-M-dependent gene expression	1	181.3×	0.013	ACTL6A
RMTs methylate histone arginines	1	146.4×	0.014	ACTL6A
Transcriptional regulation by RUNX1	1	146.4×	0.014	ACTL6A
Deubiquitination	1	124.1×	0.014	ACTL6A
UCH proteinases	1	124.1×	0.014	ACTL6A
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	1	117.7×	0.014	ACTL6A
MITF-M-regulated melanocyte development	1	114.2×	0.014	ACTL6A
DNA Repair	1	98.5×	0.016	ACTL6A
Chromatin organization	1	81.6×	0.017	ACTL6A
HATs acetylate histones	1	79.3×	0.017	ACTL6A
Chromatin modifying enzymes	1	72.3×	0.018	ACTL6A
Epigenetic regulation of gene expression	1	71.4×	0.018	ACTL6A
RNA Polymerase II Transcription	1	22.5×	0.054	ACTL6A
Post-translational protein modification	1	19.2×	0.060	ACTL6A
Gene expression (Transcription)	1	17.8×	0.063	ACTL6A
Generic Transcription Pathway	1	15.1×	0.071	ACTL6A
Developmental Biology	1	14.5×	0.072	ACTL6A
Metabolism of proteins	1	12.4×	0.081	ACTL6A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of telomere maintenance in response to DNA damage	1	1123.5×	0.005	ACTL6A
regulation of DNA strand elongation	1	1053.2×	0.005	ACTL6A
neural retina development	1	936.2×	0.005	ACTL6A
regulation of chromosome organization	1	936.2×	0.005	ACTL6A
blastocyst formation	1	766.0×	0.005	ACTL6A
regulation of G0 to G1 transition	1	674.1×	0.005	ACTL6A
regulation of nucleotide-excision repair	1	601.9×	0.005	ACTL6A
regulation of double-strand break repair	1	581.1×	0.005	ACTL6A
spinal cord development	1	510.7×	0.005	ACTL6A
regulation of mitotic metaphase/anaphase transition	1	495.6×	0.005	ACTL6A
positive regulation of T cell differentiation	1	455.5×	0.005	ACTL6A
positive regulation of double-strand break repair via homologous recombination	1	383.0×	0.005	ACTL6A
regulation of DNA replication	1	366.4×	0.005	ACTL6A
positive regulation of myoblast differentiation	1	366.4×	0.005	ACTL6A
positive regulation of DNA repair	1	358.6×	0.005	ACTL6A
positive regulation of stem cell population maintenance	1	343.9×	0.005	ACTL6A
positive regulation of double-strand break repair	1	343.9×	0.005	ACTL6A
DNA recombination	1	337.0×	0.005	ACTL6A
regulation of embryonic development	1	330.4×	0.005	ACTL6A
regulation of G1/S transition of mitotic cell cycle	1	306.4×	0.005	ACTL6A
negative regulation of cell differentiation	1	285.6×	0.005	ACTL6A
regulation of DNA repair	1	276.3×	0.005	ACTL6A
telomere maintenance	1	267.5×	0.005	ACTL6A
positive regulation of cell differentiation	1	267.5×	0.005	ACTL6A
regulation of apoptotic process	1	83.4×	0.016	ACTL6A
regulation of cell cycle	1	74.6×	0.017	ACTL6A
chromatin remodeling	1	73.0×	0.017	ACTL6A
DNA repair	1	63.8×	0.019	ACTL6A
nervous system development	1	45.9×	0.026	ACTL6A
positive regulation of cell population proliferation	1	33.6×	0.034	ACTL6A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACTL6A	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	ACTL6A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ACTL6A	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	ACTL6A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	ACTL6A
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.