# NM_001106.4(ACVR2B):c.1452G>A (p.Ser484=)

https://sugi.bio/variant/acvr2b-p-ser484

## Summary

**ACVR2B p.Ser484= (c.1452G>A)** is classified **Benign/Likely benign** in ACVR2B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-25). Rare (popmax 0.152%, eas); Associated with heterotaxy, visceral, 4, autosomal.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs56280856 · 2 submitters · 1 linked condition · rare (popmax 0.152%, eas)

## For patients & families {#patients}

This is a change in the ACVR2B gene that is classified as benign/likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to heterotaxy, visceral, 4, autosomal.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024918/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACVR2B](https://sugi.bio/atlas/gene/ACVR2B/) |
| Protein change (HGVS p.) | p.Ser484= |
| Coding change (HGVS c.) | c.1452G>A |
| MANE Select transcript | [NM_001106](https://www.ncbi.nlm.nih.gov/nuccore/NM_001106) |
| dbSNP | [rs56280856](https://www.ncbi.nlm.nih.gov/snp/rs56280856/) |
| Variant type | single nucleotide variant |
| Location | chr3:38483245-38483245 (GRCh38) |
| ClinVar | [VCV344919](https://www.ncbi.nlm.nih.gov/clinvar/variation/344919/) |

**All HGVS expressions:** `NC_000003.11:g.38524736G>A`, `NC_000003.12:g.38483245G>A`, `NG_011791.1:g.33947G>A`, `NM_001106.4:c.1452G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.28) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -3.089, GERP -4.08 — fast-evolving / accelerated position
- CADD: **PHRED 14.23**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.28**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.28**.
- Pangolin: Δ**0.38** (gain), gain 0.38 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.152%** (eas) · FAF95 0.123% · FAF99 0.112% · 68/44,872 in the highest group · 142/1,614,004 alleles overall — rare (popmax 0.152%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.152% | 660 |
| Remaining individuals (not grpmax-eligible) | 0.0656% | 1,525 |
| African / African-American | 0.0294% | 3,407 |
| Admixed American | 0.00667% | 15,002 |
| European (non-Finnish) | 0.000593% | 168,573 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ACVR2B** population constraint: LOEUF 0.408, pLI 0.99995, missense-Z 3.0549. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.18, 60% of residues very-high.

**9 experimental structure(s)** (PDB): [2H62](https://www.rcsb.org/structure/2H62), [2QLU](https://www.rcsb.org/structure/2QLU), [4FAO](https://www.rcsb.org/structure/4FAO), [5NGV](https://www.rcsb.org/structure/5NGV), [5NHR](https://www.rcsb.org/structure/5NHR), [7MRZ](https://www.rcsb.org/structure/7MRZ).

## What this gene does {#gene-function}

*Describes the biological roles of ACVR2B (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ACVR2B's established molecular role includes protein serine/threonine kinase activity.


### Pathways affected {#pathways}

ACVR2B participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Signaling by BMP](https://reactome.org/content/detail/R-HSA-201451) | curated |
| [Regulation of signaling by NODAL](https://reactome.org/content/detail/R-HSA-1433617) | electronic |
| [Signaling by Activin](https://reactome.org/content/detail/R-HSA-1502540) | electronic |
| [Signaling by NODAL](https://reactome.org/content/detail/R-HSA-1181150) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein serine/threonine kinase activity, activin receptor activity, type II, growth factor binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of DNA-templated transcription, intracellular iron ion homeostasis, signal transduction, anterior/posterior pattern specification, positive regulation of bone mineralization.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-25.

**Submitter consensus:** conflicting (1 Likely benign, 1 Benign).

**Submission history:** 2 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-05-25 |

## Associated conditions {#conditions}

[heterotaxy, visceral, 4, autosomal](https://sugi.bio/atlas/disease/heterotaxy-visceral-4-autosomal/).

**Reported phenotype names (ClinVar):** Heterotaxy, visceral, 4, autosomal.

## Similar variants {#similar}

Related ACVR2B variant pages (same residue, condition, or type): [ACVR2B p.Ser484Leu](/variant/acvr2b-p-ser484leu), [ACVR2B c.*4984T>C](/variant/acvr2b-c-star-4984t-c), [ACVR2B c.*9473T>C](/variant/acvr2b-c-star-9473t-c), [ACVR2B p.Arg161Trp](/variant/acvr2b-p-arg161trp), [ACVR2B p.Arg163His](/variant/acvr2b-p-arg163his), [ACVR2B p.Arg21His](/variant/acvr2b-p-arg21his), [ACVR2B p.Arg309His](/variant/acvr2b-p-arg309his), [ACVR2B p.Arg482Gln](/variant/acvr2b-p-arg482gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 344919). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*