ACVR1

Chr 2AD

activin A receptor type 1

Also known as: ACTRI, ACVR1A, ACVRLK2, ALK2, FOP, SKR1, TSRI

NCBI Gene: 90ENSG00000115170UniProt: Q04771OMIM: 102576

ACVR1 encodes a bone morphogenetic protein (BMP) type I receptor that forms complexes with type II receptors to transduce BMP signaling through SMAD1/5/8 phosphorylation, playing essential roles in bone, cartilage, heart, nervous system, and reproductive development. Mutations cause fibrodysplasia ossificans progressiva, a rare disorder characterized by progressive heterotopic ossification and chondrification of soft tissues. The condition follows autosomal dominant inheritance and typically presents in early childhood with progressive restriction of movement due to ectopic bone formation.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
GOFmechanismADLOEUF 0.451 OMIM phenotype
Clinical Summary— ACVR1
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Gene-Disease Validity (ClinGen)
fibrodysplasia ossificans progressiva · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
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ClinVar Variants
27 unique Pathogenic / Likely Pathogenic· 211 VUS of 460 total submissions
Explore recent and relevant literature in Research Assistant →
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GeneReview available — ACVR1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.45LOEUF
pLI 0.325
Z-score 3.64
OE 0.23 (0.13–0.45)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.34Z-score
OE missense 0.61 (0.54–0.69)
176 obs / 287.5 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.23 (0.13–0.45)
0≤0.351.4
Missense OE0.61 (0.54–0.69)
0≤0.61.4
Synonymous OE0.96
0≤1.21.6
LoF obs/exp: 6 / 26.1Missense obs/exp: 176 / 287.5Syn Z: 0.36
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongACVR1-related fibrodysplasia ossificans progressivaGOFAD
DN
0.5674th %ile
GOF
0.6541th %ile
LOF
0.48top 25%

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median · 1 literature citation

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

GOFGain-of-function mutations in the Type I Bone Morphogenic Protein (BMP) receptor ACVR1 have been identified in two diseases: Fibrodysplasia Ossificans Progressiva (FOP), a rare autosomal dominant disorder characterized by genetically driven heterotopic ossification, and in 20-25% of Diffuse IntrinsiPMID:28780023

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

460 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic4
VUS211
Likely Benign160
Benign44
Conflicting7
23
Pathogenic
4
Likely Pathogenic
211
VUS
160
Likely Benign
44
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
8
15
0
23
Likely Pathogenic
0
2
2
0
4
VUS
15
170
20
6
211
Likely Benign
1
13
58
88
160
Benign
0
2
34
8
44
Conflicting
—7
Total16195129102449

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

View in ClinVar →

Protein Context — Lollipop Plot

ACVR1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients