MACF1

Chr 1AD

microtubule actin crosslinking factor 1

Also known as: ABP620, ACF7, KIAA0754, LIS9, Lnc-PMIF, MACF, OFC4

NCBI Gene: 23499ENSG00000127603UniProt: Q9UPN3

This gene encodes a large protein containing numerous spectrin and leucine-rich repeat (LRR) domains. The encoded protein is a member of a family of proteins that form bridges between different cytoskeletal elements. This protein facilitates actin-microtubule interactions at the cell periphery and couples the microtubule network to cellular junctions. Alternative splicing results in multiple transcript variants, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, May 2013]

Primary Disease Associations & Inheritance

Lissencephaly 9 with complex brainstem malformationMIM #618325
AD
518
ClinVar variants
3
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— MACF1
🧬
Gene-Disease Validity (ClinGen)
lissencephaly spectrum disorder with complex brainstem malformation · ADModerate

Moderate evidence — consider for supplementary testing

⚡
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
3 Pathogenic / Likely Pathogenic· 283 VUS of 518 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.08LOEUF
pLI 1.000
Z-score 15.61
OE 0.06 (0.04–0.08)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.43Z-score
OE missense 0.82 (0.79–0.85)
2325 obs / 2840.0 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.06 (0.04–0.08)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.79–0.85)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02
0≤1.21.6
LoF obs/exp: 18 / 318.8Missense obs/exp: 2325 / 2840.0Syn Z: -0.63

ClinVar Variant Classifications

518 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic3
VUS283
Likely Benign190
Benign25
Conflicting17
3
Likely Pathogenic
283
VUS
190
Likely Benign
25
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
0
0
0
Likely Pathogenic
1
1
1
0
3
VUS
12
249
20
2
283
Likely Benign
0
112
30
48
190
Benign
0
8
9
8
25
Conflicting
—17
Total133706058518

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

View in ClinVar →

Protein Context — Lollipop Plot

MACF1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

MACF1-related defects in neuronal migration and axon guidance

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Lissencephaly 9 with complex brainstem malformation

MIM #618325

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — MACF1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical and genetic characterisation of a large Indian congenital myasthenic syndrome cohort.
Polavarapu K et al.·Brain
2024Cohort
A clinical and genotype-phenotype analysis of MACF1 variants.
Dekker J et al.·Am J Hum Genet
2025
MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.
Dobyns WB et al.·Am J Hum Genet
2018
Identification of MACF1 as a causative gene of generalised epilepsy.
Lei XY et al.·J Med Genet
2025
THADA, SDHAF4, and MACF1 Gene Polymorphisms and Placental Expression in Women with Gestational Diabetes.
Ustianowski P et al.·Genes (Basel)
2022
Transcriptional activation of MACF1 by NR2F1 drives WNT-mediated focal adhesion and metastasis in lung adenocarcinoma.
Zhou Y et al.·Eur J Med Res
2025
Genetic etiology of ventriculomegaly in 73 fetuses identified by High-Throughput sequencing.
Chenyue Z et al.·Sci Rep
2025
Microtubule-Actin Crosslinking Factor 1 and Plakins as Therapeutic Drug Targets.
Quick QA·Int J Mol Sci
2018Review
Expression and Clinical Significance of Microtubule-Actin Cross-Linking Factor 1 in Serous Ovarian Cancer.
Liu L et al.·Recent Pat Anticancer Drug Discov
2021
Identification and validation of prognostic biomarkers in ccRCC: immune-stromal score and survival prediction.
Lyu F et al.·BMC Cancer
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools