# NM_001103.4(ACTN2):c.2056A>G (p.Ile686Val)

https://sugi.bio/variant/actn2-p-ile686val

## Summary

**ACTN2 p.Ile686Val (c.2056A>G)** is classified **Conflicting classifications of pathogenicity** in ACTN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-06). AlphaMissense: likely benign (0.065); Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs534607483 · 2 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the ACTN2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Cardiovascular phenotype.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACTN2](https://sugi.bio/atlas/gene/ACTN2/) |
| Protein change (HGVS p.) | p.Ile686Val |
| Coding change (HGVS c.) | c.2056A>G |
| MANE Select transcript | [NM_001103](https://www.ncbi.nlm.nih.gov/nuccore/NM_001103) |
| dbSNP | [rs534607483](https://www.ncbi.nlm.nih.gov/snp/rs534607483/) |
| Variant type | single nucleotide variant |
| Location | chr1:236755100-236755100 (GRCh38) |
| ClinVar | [VCV1785131](https://www.ncbi.nlm.nih.gov/clinvar/variation/1785131/) |

**All HGVS expressions:** `LRG_436:g.95960A>G`, `LRG_436t1:c.2056A>G`, `NC_000001.10:g.236918400A>G`, `NC_000001.11:g.236755100A>G`, `NG_009081.2:g.95960A>G`, `NM_001103.4:c.2056A>G`, `NM_001278343.2:c.2056A>G`, `NM_001278344.2:c.1432A>G`, `NM_001412150.1:c.1306A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.065)
- REVEL 0.081 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.057 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.703, GERP 0.024, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 17.47**. 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.*
- Regional missense constraint: **o/e 0.90** across the covering region of the MANE Select transcript (236,737,190–236,762,616), spanning 25,426 bp. Chi-square p 0.0054. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · FAF95 0.000292% · FAF99 0.000211% · 1/60,032 in the highest group · 9/1,614,226 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 60,032 |
| European (non-Finnish) | 0.000678% | 147,505 |

*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}

**ACTN2** population constraint: LOEUF 0.432, pLI 0.99996, missense-Z 2.2746. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **ACTN2-related cardiac and skeletal myopathy** — Definitive (AD)

## Protein context {#protein}

Residue **686** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 84.88, 47% of residues very-high.

**18 experimental structure(s)** (PDB): [1H8B](https://www.rcsb.org/structure/1H8B), [1HCI](https://www.rcsb.org/structure/1HCI), [1QUU](https://www.rcsb.org/structure/1QUU), [4D1E](https://www.rcsb.org/structure/4D1E), [5A36](https://www.rcsb.org/structure/5A36), [5A37](https://www.rcsb.org/structure/5A37) — incl. mutant structure 9SIR.

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

*Describes the biological roles of ACTN2 (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:** ACTN2's established molecular role includes phosphatidylinositol-4,5-bisphosphate binding.


### Pathways affected {#pathways}

ACTN2 participates in **9 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Striated Muscle Contraction](https://reactome.org/content/detail/R-HSA-390522) | curated |
| [Assembly and cell surface presentation of NMDA receptors](https://reactome.org/content/detail/R-HSA-9609736) | electronic |
| [Long-term potentiation](https://reactome.org/content/detail/R-HSA-9620244) | electronic |
| [Negative regulation of NMDA receptor-mediated neuronal transmission](https://reactome.org/content/detail/R-HSA-9617324) | electronic |
| [Nephrin family interactions](https://reactome.org/content/detail/R-HSA-373753) | electronic |
| [Ras activation upon Ca2+ influx through NMDA receptor](https://reactome.org/content/detail/R-HSA-442982) | electronic |
| [Unblocking of NMDA receptors, glutamate binding and activation](https://reactome.org/content/detail/R-HSA-438066) | electronic |

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

**Molecular function:** phosphatidylinositol-4,5-bisphosphate binding, cytoskeletal protein binding, protein domain specific binding, titin binding, identical protein binding, transmembrane transporter binding.

**Biological process:** microspike assembly, regulation of membrane potential, negative regulation of potassium ion transport, positive regulation of potassium ion transport, sarcomere organization, focal adhesion assembly.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-07-06.

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

**Submission history:** 2 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-06 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [dilated cardiomyopathy 1AA](https://sugi.bio/atlas/disease/dilated-cardiomyopathy-1aa/), [familial hypertrophic cardiomyopathy](https://sugi.bio/atlas/disease/familial-hypertrophic-cardiomyopathy/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, Dilated cardiomyopathy 1AA, Primary familial hypertrophic cardiomyopathy, CARDIOMYOPATHY, DILATED, 1AA, WITH OR WITHOUT LEFT VENTRICULAR NONCOMPACTION, CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 23, WITH OR WITHOUT LEFT VENTRICULAR NONCOMPACTION, Cardiomyopathy, dilated, 1AA, with or without LVNC.

## Similar variants {#similar}

Related ACTN2 variant pages (same residue, condition, or type): [ACTN2 p.Ile686Leu](/variant/actn2-p-ile686leu), [ACTN2 p.Ile686del](/variant/actn2-p-ile686del), [ACTN2 p.Ala119Thr](/variant/actn2-p-ala119thr), [ACTN2 p.Thr247Met](/variant/actn2-p-thr247met), [ACTN2 c.1107+3G>A](/variant/actn2-c-1107-plus-3g-a), [ACTN2 c.1108-10A>G](/variant/actn2-c-1108-minus-10a-g), [ACTN2 c.1255+1G>C](/variant/actn2-c-1255-plus-1g-c), [ACTN2 c.126+2T>G](/variant/actn2-c-126-plus-2t-g).

### 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 1785131). 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.*