ACTG1

Chr 17AD

actin gamma 1

Also known as: ACT, ACTG, DFNA20, DFNA26, HEL-176

NCBI Gene: 71 ENSG00000184009 UniProt: P63261 OMIM: 102560

The protein is a cytoplasmic actin that maintains the cytoskeleton and mediates internal cell motility in all cell types. Mutations cause autosomal dominant Baraitser-Winter syndrome 2 and autosomal dominant nonsyndromic sensorineural progressive hearing loss (DFNA20/26). The pathogenic mechanism involves dominant-negative effects of the mutant protein.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Actins are highly conserved proteins that are involved in various types of cell motility and in maintenance of the cytoskeleton. Three main groups of actin isoforms have been identified in vertebrate animals: alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins co-exist in most cell types as components of the cytoskeleton and as mediators of internal cell motility. Actin gamma 1, encoded by this gene, is a cytoplasmic actin found in all cell types. Mutations in this gene are associated with DFNA20/26, a subtype of autosomal dominant non-syndromic sensorineural progressive hearing loss and also with Baraitser-Winter syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.862 OMIM phenotypes

Clinical Summary— ACTG1

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Gene-Disease Validity (ClinGen)

Baraitser-winter syndrome 2 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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

60 unique Pathogenic / Likely Pathogenic· 185 VUS of 724 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ACTG1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.86LOEUF

pLI 0.005

Z-score 1.95

OE 0.43 (0.24–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

3.16Z-score

OE missense 0.37 (0.30–0.45)

72 obs / 196.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.43 (0.24–0.86)

0≤0.351.4

Missense OE?0.37 (0.30–0.45)

0≤0.61.4

Synonymous OE?3.73

0≤1.21.6

LoF obs/exp: 6 / 13.8Missense obs/exp: 72 / 196.7Syn Z: -18.97

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveACTG1-related Baraitser-Winter syndromeGOFAD

limitedACTG1-related isolated ocular colobomaOTHERAD

This gene — mechanism propensity

0.7034th %ile

GOF

0.5366th %ile

LOF

0.3164th %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

GOF1 literature citation · 100% of P/LP are missense

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.

Literature Evidence

GOFBaraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode beta- and gamma-actins.1

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

References

1.PMID 25052316 ↗

ClinVar Variant Classifications

724 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15

Likely Pathogenic45

VUS185

Likely Benign361

Benign59

Conflicting43

Pathogenic

Likely Pathogenic

185

VUS

361

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	15	0	0	15
Likely Pathogenic	0	45	0	0	45
VUS	16	145	15	9	185
Likely Benign	0	2	118	241	361
Benign	0	0	45	14	59
Conflicting	—				43
Total	16	207	178	264	708

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap ACTG1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →