ACVR1

Chr 2AD

activin A receptor type 1

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

NCBI Gene: 90 ENSG00000115170 UniProt: Q04771 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I ( I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. This gene encodes activin A type I receptor which signals a particular transcriptional response in concert with activin type II receptors. Mutations in this gene are associated with fibrodysplasia ossificans progressive. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Fibrodysplasia ossificans progressivaMIM #135100

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.45

LOEUF

GOF

Mechanism· G2P

📖

GeneReview available — ACVR1

Authoritative clinical overview · Recommended first read

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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 OE?0.23 (0.13–0.45)

0≤0.351.4

Missense OE?0.61 (0.54–0.69)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 6 / 26.1Missense obs/exp: 176 / 287.5Syn Z: 0.36

Background carrier burden — how many people carry a rare variant somewhere in ACVR1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 210

500 rare PASS variants

Rare truncating (LoF)

1 in 3,300

72 rare PASS variants

Rare synonymous (reference)

1 in 190

229 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ACVR1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 200	1 in 3,900
South Asian	~43k	1 in 120	1 in 1,100
Remaining (unassigned)	~30k	1 in 180	1 in 3,800
European (Finnish)	~27k	1 in 670	≈ 1 in 27,000
Admixed American	~22k	1 in 290	1 in 3,800
African / African American	~21k	1 in 200	1 in 2,900
East Asian	~20k	1 in 210	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 770	1 in 1,400
Middle Eastern	~2,884	1 in 210	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓