The ACVR1 NM_001111067.4:c.617G>A (NP_001104537.1:p.(Arg206His)) missense variant has previously been reported in somatic cancers (COSMIC; COSV55115924, n = 27 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: Three independent assay systems showed weakened FKBP12 inhibition and increased BMP-pathway signaling for exact ACVR1 R206H. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.ACVR1, also known as ALK2, encodes a cell-surface receptor that helps transmit signals from bone morphogenetic proteins and activins to regulate cell survival, growth, and differentiation. Activating changes in ACVR1 cause fibrodysplasia ossificans progressiva, a rare disorder in which bone forms abnormally in soft tissues. ACVR1 alterations also occur in diffuse intrinsic pontine glioma, a type of childhood brain cancer, where the gene acts as an oncogenic driver.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, strong: the exact ACVR1 p.Arg206His substitution is repeatedly reported as the recurrent disease-causing FOP mutation.
Met at moderate strength: three independent assay systems showed weakened FKBP12 inhibition and increased BMP-pathway signaling for exact ACVR1 R206H.
Met at supporting: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, satisfying the <=0.0001 PM2 threshold.
Met: the affected proband carried c.617G>A while both parents and a brother were wild type, without documented parentage confirmation.
Met strong: missense REVEL score 0.948 exceeds the PP3 strong threshold of 0.932.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PS1 and PP3 at strong strength satisfy the generic ACMG/AMP rule requiring two strong pathogenic criteria, with PS3, PM6, and PM2 also applied.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1 allele counts were not recorded for this variant.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.948. Refer to the recorded PP3/BP4 rationale for interpretation.
19 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV55115924, n = 27 times).
This variant lies in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 9 not met · 9 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The segregation evidence supports PM6 but not PS2 because parental variant testing was reported without documented confirmation of maternity and paternity; PP1 and BS4 lack the required informative affected-family-member data.
These criteria were adjudicated under generic ACMG/AMP because no ACVR1 VCEP specification was retrieved.
PS4 is not assessed because the literature provides affected-case observations but no verified control counts or variant-specific OR/RR with a 95% CI.
PP4 is not assessed because patient-specific phenotype and family history are absent.
PP5 and BP6 are not triggered because ClinVar has zero expert-panel submissions and generic ordinary submissions do not qualify; BP5 lacks an alternate molecular diagnosis.
No criteria match.
The variant is ACVR1 p.Arg206His (c.617G>A). Multiple peer-reviewed reports identify this exact substitution as the recurrent mutation causing fibrodysplasia ossificans progressiva, including the original clinical report and subsequent structural and functional studies. The same amino-acid change has therefore been previously established as pathogenic, and the reported evidence is protein-level rather than a splice-only observation.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PS3 is met at moderate strength. The exact ACVR1 c.617G>A (p.Arg206His/R206H) variant was tested in multiple independent functional systems. Chaikuad et al. (PMID:22977237) used C2C12 BRE-luciferase signaling assays, FKBP12 co-immunoprecipitation, and structural analysis, showing moderate ligand-independent gain of function and weakened inhibitory regulation. Huse et al. (PMID:21525719) used three orthogonal purified-protein interaction assays—native PAGE, size-exclusion chromatography, and biolayer interferometry—and measured approximately threefold weaker FKBP12 affinity for R206H than wild type (BLI Kd 0.58 ± 0.074 µM versus 0.19 ± 0.024 µM), while transparently reporting nonspecific-interaction limitations at lower pH. Castel et al. (PMID:24705252) showed increased phospho-Smad1/5/8 signaling in R206H overexpression experiments in the context of a DIPG cohort. Together, these variant-specific in vitro results demonstrate dysregulated ACVR1 regulation and increased BMP-pathway signaling, directly supporting a damaging/gain-of-function effect. Moderate rather than the highest strength is used because the supplied evidence does not establish validation and reproducibility in a clinical diagnostic laboratory setting.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PM2 is met at supporting strength. The exact ACVR1 NM_001111067.4:c.617G>A (p.Arg206His) variant is absent from gnomAD v2.1 and gnomAD v4.1; the non-cancer gnomAD v2.1 and v3.1 checks also report absence. This satisfies the supplied generic PM2 supporting threshold of <=0.0001.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Lin et al. reported the exact ACVR1 c.617G>A variant in a clinically affected child with FOP and found it absent from both parents and a brother. This supports an assumed de novo event, while the publication does not document confirmation of maternity and paternity, matching the PM6 definition.
Assumed de novo, but without confirmation of paternity and maternity.
The variant is a missense substitution, ACVR1 NM_001111067.4:c.617G>A (p.Arg206His), so the governing generic rule requires the missense REVEL path only; SpliceAI is not used for PP3/BP4 in this situation. REVEL is 0.948, which meets the generic PP3 strong threshold of >= 0.932 from the ClinGen SVI calibration (Pejaver et al. 2022, PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (strong): >= 0.932 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The exact ACVR1 c.617G>A variant was heterozygous in the proband and absent from both parents in the reported Taiwanese FOP case, supporting de novo occurrence. However, the report does not document confirmation of maternity and paternity, which is required for PS2 under the governing definition; parental testing alone is insufficient to establish the required parentage confirmation.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The governing rule requires a reputable pathogenic report whose evidence is unavailable for independent evaluation. The exact-variant ClinVar record is Pathogenic, but the audit shows expert_panel_submissions = 0; the available records are ordinary laboratory or literature-only assertions. The published pathogenic association is available for independent evaluation, and generic ClinVar assertions do not trigger PP5 under the specified rule. Therefore PP5 is not met.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The exact variant NM_001111067.4:c.617G>A (ACVR1 p.Arg206His) was absent from gnomAD v2.1 and gnomAD v4.1, so no filtering allele frequency or grpmax FAF reaches the generic stand-alone threshold of >=0.05. The case also contains no evidence of a high-frequency founder or reduced-penetrance allele that would support a benign stand-alone conclusion despite the established disease association.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met. The exact variant was absent from gnomAD v2.1 and gnomAD v4.1, so the required filtering allele frequency/grpmax FAF is 0 or unavailable rather than greater than the expected frequency for FOP. Because no elevated population frequency is present, the generic 1% default and a maximum-credible-allele-frequency calculation do not alter the conclusion.
Allele frequency is greater than expected for the disorder.
BS2 is not met. The supplied case evidence contains no observation of this variant in a healthy adult, whether as a heterozygote, homozygote, or hemizygote. The available gnomAD records establish absence of the allele but do not provide a healthy-adult carrier observation that satisfies BS2.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
The reviewed ACVR1 disease literature identifies an activating missense mechanism, including the recurrent p.Arg206His substitution in FOP, rather than a disease model in which primarily truncating variants are known to cause disease. The defining BP1 condition is therefore not satisfied.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is a missense substitution, so the governing generic rule requires evaluation by REVEL only; the SpliceAI score cannot substitute for an uninformative missense REVEL result. REVEL is 0.948, which does not meet any benign BP4 threshold (supporting <= 0.29, moderate <= 0.183, or strong <= 0.016). BayesDel is not used because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). ... BP4 (strong): <= 0.016 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... BP4 (moderate): <= 0.183 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The governing rule requires the variant to be found in a case with an alternate molecular basis for disease. The supplied case evidence documents the ACVR1 variant but no alternate molecular diagnosis explaining the same case. Therefore BP5 is not met.
Variant found in a case with an alternate molecular basis for disease.
The governing rule requires a reputable benign report whose evidence is unavailable for independent evaluation. The exact-variant ClinVar record is Pathogenic, not benign or likely benign, and has expert_panel_submissions = 0. No exact-variant reputable benign or likely-benign assertion is documented. Ordinary submissions, aggregate labels, and non-expert assertions cannot trigger BP6, so BP6 is not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The governing rule requires a significant increase in affected individuals and, under its note, an RR or OR >5.0 with a confidence interval that does not include 1.0. PMID:24705252 reports the exact variant in 1 of 52 DIPG samples, but provides no unaffected or population control comparison and no variant-specific OR or 95% CI. PMID:22977237 is a functional study and its extract reports no patient-level or population-frequency comparison. The literature-pass PS4 leads PMID:16642017 and PMID:17351709 report affected FOP cases in their titles, but the supplied material does not provide verified affected/control counts; PMID:18830232 is listed as an unresolved PS4 lead without a usable source record. Therefore no OR or 95% CI can be calculated, and PS4 cannot be assessed rather than called not_met.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
ACVR1 p.Arg206His is reported within the glycine-serine-rich regulatory domain, and the reviewed literature describes this region as functionally important. However, no VCEP domain table applies and the available case evidence does not establish the required absence of benign variation across the relevant domain or hotspot. The criterion cannot be completed from the available evidence.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The reviewed evidence documents ACVR1 p.Arg206His but does not identify a different missense substitution at residue 206 that has independently been established as pathogenic. The same-residue comparator collection contains zero confirmed candidates, so PM5 cannot be assessed.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
The available case report describes one affected proband and does not provide multiple affected family members carrying the variant with which to evaluate co-segregation. The absence of affected relatives in this report is not evidence that the variant fails to segregate.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The evidence supports that ACVR1 disease can involve pathogenic missense variation, but no gene-level analysis establishing a low rate of benign missense variation is provided. Because both parts of the PP2 definition are required and the benign-missense rate is unavailable, PP2 is not assessed.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The governing rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The case materials identify ACVR1 c.617G>A (p.Arg206His) and describe FOP literature, but do not provide this patient's phenotype or family history. Published descriptions of FOP cannot substitute for patient-level clinical findings, so PP4 cannot be assessed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS3 is not assessed because the reviewed variant-specific functional evidence is damaging rather than benign: R206H showed reduced FKBP12 binding, ligand-independent signaling, and increased phospho-Smad1/5/8 signaling. No well-established assay result showing no damaging effect on protein function or splicing was supplied, and damaging functional evidence cannot be converted into a benign functional criterion.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The reported relatives tested for ACVR1 c.617G>A were unaffected family members, not affected members who lacked the variant. Therefore, the available data do not demonstrate lack of segregation in affected family members and cannot establish BS4.
Lack of segregation in affected members of a family.
The available affected-proband report documents the variant as heterozygous and de novo, with wild-type results in the parents and brother, but does not document a second pathogenic variant in trans or a pathogenic variant in cis. Therefore BP2 cannot be assessed from the available phase and allelic data.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001111067.4:c.617G>A in ACVR1 is a missense substitution predicted to produce NP_001104537.1:p.(Arg206His). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for ACVR1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM3 is not applicable because the relevant ACVR1 disorder is described as autosomal dominant, while the variant is observed as a single heterozygous change in an affected proband. No recessive-disease trans configuration is established or required for this dominant disorder.
For recessive disorders, detected in trans with a pathogenic variant ... This requires testing of parents (or offspring) to determine phase.
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001111067.4:c.617G>A in ACVR1 is a missense substitution predicted to produce NP_001104537.1:p.(Arg206His). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for ACVR1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001111067.4:c.617G>A in ACVR1 is a missense substitution predicted to produce NP_001104537.1:p.(Arg206His). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for ACVR1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001111067.4:c.617G>A in ACVR1 is a missense substitution predicted to produce NP_001104537.1:p.(Arg206His). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for ACVR1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in ACVR1, mapped onto the exon structure of NM_001111067.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, ACVR1 NM_001111067.4:c.617G>A (p.Arg206His), so the governing generic rule requires the missense REVEL path only; SpliceAI is not used for PP3/BP4 in this situation. REVEL is 0.948, which meets the generic PP3 strong threshold of >= 0.932 from the ClinGen SVI calibration (Pejaver et al. 2022, PMID:36413997). BayesDel is not used because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (strong): >= 0.932 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense substitution, so the governing generic rule requires evaluation by REVEL only; the SpliceAI score cannot substitute for an uninformative missense REVEL result. REVEL is 0.948, which does not meet any benign BP4 threshold (supporting <= 0.29, moderate <= 0.183, or strong <= 0.016). BayesDel is not used because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). ... BP4 (strong): <= 0.016 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... BP4 (moderate): <= 0.183 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001111067.4:c.617G>A in ACVR1 is a missense substitution predicted to produce NP_001104537.1:p.(Arg206His). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for ACVR1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.948. BayesDel score = 0.539395.
10 paper records listed. 4 cited in the classification.
Direct sequence analysis identified a 617G–A nucleotide mutation in the patient but not in her parents or brother.
Location Abstract; Results, DNA sequence analysis; Discussion
Context Single-patient clinical report involving a 3-year-old Taiwanese girl with FOP; ACVR1 exon/promoter PCR, direct Sanger sequencing, and Cac8I restriction-enzyme confirmation were performed on familial blood samples.
Nevertheless, about a 3-fold decrease in affinity for the mutant was determined; this is more consistent with the native gel than the SEC/PAGE analyses.
Location Abstract; Results, Quantitative Analyses by BLI Optical Biosensor; Fig. 3; Discussion
Context Three independent in vitro interaction assays using purified wild-type and R206H ALK2 kinase domains and FKBP12: native polyacrylamide gel electrophoresis, HPLC size-exclusion chromatography, and Octet biolayer interferometry; lower-pH assays were affected by nonspecific binding.
Linkage analysis led to the identification of a recurrent heterozygous mutation (617G → A; R206H) in the type I BMP receptor ALK2 (ACVR1).
Location Introduction; Results, Figure 1B and accompanying paragraph; Results, Figure 2; Results section "FOP Mutations Destabilize the Inactive State"; Discussion
Context Functional testing used C2C12 cells transfected with ALK2 constructs and a BRE-luciferase reporter, with untreated, BMP4/BMP6-treated, and FK506-treated conditions. FKBP12 binding was assessed by co-transfection of FLAG-tagged ALK2 and HA-tagged FKBP12 followed by immunoprecipitation in C2C12 and HEK293 cells. Structural interpretation was based on a 2.35 Å crystal structure of the ALK2 GS/kinase region–FKBP12 complex.
These were restricted to the specific codons 328 (c.983G>T, p.G328V, two cases; c.983G>A, p.G328E, two cases), 258 (c.772C>T, p.R258G, one case), and 356 (c.1067G>A p.G356D), all within the serine/threonine kinase domain; and 206 (c.617G>A, p.R206H, one case), within the glycine-serine (GS)-rich domain.
Location Results, paragraph describing recurrent ACVR1 mutations; Figure 2a; functional results in Figure 3b
Context DIPG tumour cohort of 52 samples, including whole-genome/exome sequencing and Sanger validation; patient-derived DIPG cell cultures with ACVR1 R206H or G328V; ACVR1 mutant overexpression followed by phospho-Smad1/5/8 Western blotting; RNA sequencing and cDNA Sanger sequencing for allelic expression.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (19 clinical laboratories). (ClinVarID = 18309)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.948. BayesDel score = 0.539395.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55115924, n = 27 times).
This variant lies in a statistically significant hotspot.