ACVR1

protein-coding

activin A receptor type 1, the group of Type 1 receptor serine/threonine kinases

Gene summary

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]

Previous symbols:

ACVRLK2

MANE transcript

NM_001111067.4

Inheritance

ClinVar variants

P:10U:204B:122

Top phenotype

Fibrodysplasia ossificans progressiva

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr2:157,736,251-157,876,330

External References & Databases

Ensembl (ENSG00000115170)

Transcript & Mutation Effects

hg38 • Region Span ~140.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*ACVR1* was first reported in relation to autosomal dominant congenital heart disease in 2009 (Smith et al., PMID: 19506109). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, fibrodysplasia ossificans progressiva and congenital heart disease have been split as two separate disease entities. Two unique missense variants have been reported in two probands in one publication (PMIDs: 19506109). The gene-disease relationship is supported by a knockout mouse models that show *Acvr1*-mutant mice display cardiovascular defects including persistent truncus arteriosus, abnormal maturation of the aortic arch, aortic stenosis, and atrioventricular septal defects (PMIDs:15226263, 22536403, 16140292). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 08/14/2023 (SOP Version 9)

fibrodysplasia ossificans progressivaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007606

Submitter: PanelApp Australia

fibrodysplasia ossificans progressivaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007606

Submitter: Labcorp Genetics (formerly Invitae)

fibrodysplasia ossificans progressivaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007606

Submitter: Orphanet

fibrodysplasia ossificans progressivaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007606

Submitter: G2P

fibrodysplasia ossificans progressivaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007606

Submitter: Ambry Genetics

fibrodysplasia ossificans progressivaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007606

Submitter: ClinGen

ACVR1 was first reported in relation to autosomal dominant fibrodysplasia ossificans progressiva (FOP) in 2006 (Shore et al., PMID: 16642017). FOP is characterized by heterotopic ossification and malformed big toes. Nine missense variants and one indel variant that have been reported in 15 probands in seven publications (PMIDs: 16642017, 18203193, 19085907, 18830232, 21044902, 34347384, 36060212) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be gain of function. This gene-disease association is also supported by protein-protein interactions, expression data, mouse and zebrafish models, and functional alteration of patient cells (PMIDs: 22977237, 22508565, 26626181, 29307777). In summary, ACVR1 is definitively associated with autosomal dominant fibrodysplasia ossificans progressiva. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on 3/1/23 (SOP Version 9).

Clinical Genomic Database (CGD)

Fibrodysplasia ossificans progressivaAD

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 8758048; 17077940; 16642017; 17351709; 18830232; 19330033; 24259422

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACVR1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 359

Inborn genetic diseasesTotal: 45

Progressive myositis ossificansTotal: 37

not specifiedTotal: 32

ACVR1-related disorderTotal: 18

Congenital heart diseaseTotal: 2

Multiple congenital anomalies/dysmorphic syndromeTotal: 1

EpicanthusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001111067.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	100 clinvar	2 clinvar	108
missense	7 clinvar	3 clinvar	179 clinvar	17 clinvar	2 clinvar	208
nonsense			7 clinvar	1 clinvar		8
start loss			1 clinvar			1
frameshift			6 clinvar			6
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	7	3	204	118	4	336

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 96 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001111067.4	RefSeq	NP_001104537.1	9	MANE Select
ENST00000434821.7	Ensembl	ENSP00000405004.1	9	MANE Select
NM_001105.5	RefSeq	NP_001096.1	9	Standard
NM_001347663.1	RefSeq	NP_001334592.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

TGF-beta signaling pathway - Homo sapiens (human)
Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
Fluid shear stress and atherosclerosis - Homo sapiens (human)
Cytokine-cytokine receptor interaction - Homo sapiens (human)
TGF-Core

Biological Process

G1/S transition of mitotic cell cycle
branching involved in blood vessel morphogenesis
in utero embryonic development
gastrulation with mouth forming second
mesoderm formation

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
transmembrane receptor protein serine/threonine kinase activity
transforming growth factor beta-activated receptor activity
transforming growth factor beta receptor activity, type I

Cellular Component

integral component of plasma membrane
receptor complex
apical part of cell
activin receptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263640
Coding exons: 9
Length: 139417
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125745
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.34	176	288	0.612	0.0000162	3350
Missense (PolyPhen)		62	150.78	0.41119		1758
Synonymous	0.364	103	108	0.955	0.00000658	966
Loss of Function	3.64	6	26.1	0.230	0.00000142	288

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.000055	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for activin. May be involved for left-right pattern formation during embryogenesis (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.384

Intolerance Scores

LoFtool: 0.138
RVIS EVS: -0.51
RVIS percentile EVS: 21.41

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.998

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium