# NM_001106.4(ACVR2B):c.1A>G (p.Met1Val)

https://sugi.bio/variant/acvr2b-p-met1val

## Summary

**ACVR2B p.Met1Val (c.1A>G)** is classified **Uncertain significance** in ACVR2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28). No allele count reported in gnomAD v4.1 (AN 1,296,534); Associated with heterotaxy, visceral, 4, autosomal.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1559642966 · 1 submitter · 1 linked condition · no allele count reported in gnomAD v4.1 (AN 1,296,534)

## For patients & families {#patients}

This is a change in the ACVR2B gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Met1Val |
| Coding change (HGVS c.) | c.1A>G |
| dbSNP | [rs1559642966](https://www.ncbi.nlm.nih.gov/snp/rs1559642966/) |
| Variant type | single nucleotide variant |
| Location | chr3:38454323-38454323 (GRCh38) |
| ClinVar | [VCV579672](https://www.ncbi.nlm.nih.gov/clinvar/variation/579672/) |

**All HGVS expressions:** `NC_000003.11:g.38495814A>G`, `NC_000003.12:g.38454323A>G`, `NG_011791.1:g.5025A>G`, `NM_001106.4:c.1A>G`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP 10.24, GERP -0.3, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **start-loss** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 20.5**. 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: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,296,534)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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.*

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-28.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-28 |

## Associated conditions {#conditions}

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

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

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 579672). 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.*