# NM_018075.5(ANO10):c.556T>C (p.Trp186Arg)

https://sugi.bio/variant/ano10-p-trp186arg

## Summary

**ANO10 p.Trp186Arg (c.556T>C)** is classified **Uncertain significance** in ANO10 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-21). AlphaMissense: likely pathogenic (0.9961); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ANO10 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [ANO10](https://sugi.bio/atlas/gene/ANO10/) |
| Protein change (HGVS p.) | p.Trp186Arg |
| Coding change (HGVS c.) | c.556T>C |
| MANE Select transcript | [NM_018075](https://www.ncbi.nlm.nih.gov/nuccore/NM_018075) |
| Variant type | single nucleotide variant |
| Location | chr3:43580389-43580389 (GRCh38) |
| ClinVar | [VCV3369621](https://www.ncbi.nlm.nih.gov/clinvar/variation/3369621/) |

**All HGVS expressions:** `NC_000003.11:g.43621881A>G`, `NC_000003.12:g.43580389A>G`, `NG_028216.2:g.116206T>C`, `NM_001204831.3:c.556T>C`, `NM_001204832.3:c.358T>C`, `NM_001204833.3:c.223T>C`, `NM_001204834.3:c.556T>C`, `NM_001346463.2:c.556T>C`, `NM_001346464.2:c.556T>C`, `NM_001346465.2:c.556T>C`, `NM_001346466.2:c.358T>C`, `NM_001346467.2:c.556T>C`, `NM_001346468.2:c.556T>C`, `NM_001346469.2:c.358T>C`, `NM_018075.5:c.556T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9961)
- REVEL 0.823 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.131 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.135, GERP 1.78, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in ANO10 (of 3,848 modeled).
- CADD: **PHRED 29.4**. 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 0.93** across the covering region of the MANE Select transcript (43,366,909–43,605,852), spanning 238,943 bp. Chi-square p 0.041. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.57 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**ANO10** population constraint: LOEUF 1.24, pLI 3.7519e-26, missense-Z 1.0031. *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):

- **autosomal recessive spinocerebellar ataxia 10** — Definitive (AR)

## Protein context {#protein}

Residue **186** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 86.26, 55% of residues very-high.

**5 experimental structure(s)** (PDB): [5OC9](https://www.rcsb.org/structure/5OC9), [6R65](https://www.rcsb.org/structure/6R65), [6R7X](https://www.rcsb.org/structure/6R7X), [6R7Y](https://www.rcsb.org/structure/6R7Y), [6R7Z](https://www.rcsb.org/structure/6R7Z).

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

*Describes the biological roles of ANO10 (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:** ANO10's established molecular role includes calcium-activated cation channel activity. In Reactome, ANO10 is annotated in disease pathway(s) including **Induction of Cell-Cell Fusion**.

**Disease mechanism (Reactome):** ANO10 loss or alteration is curated in [Induction of Cell-Cell Fusion](https://reactome.org/content/detail/R-HSA-9733458).

### Pathways affected {#pathways}

ANO10 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Induction of Cell-Cell Fusion](https://reactome.org/content/detail/R-HSA-9733458) | curated |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

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

**Molecular function:** calcium-activated cation channel activity, intracellularly calcium-gated chloride channel activity.

**Biological process:** chloride transmembrane transport.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-02-21.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-21 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ANO10 variant pages (same residue, condition, or type): [ANO10 c.1163-9A>G](/variant/ano10-c-1163-minus-9a-g), [ANO10 c.1218+1G>C](/variant/ano10-c-1218-plus-1g-c), [ANO10 c.1219-1G>T](/variant/ano10-c-1219-minus-1g-t), [ANO10 c.139+1G>T](/variant/ano10-c-139-plus-1g-t), [ANO10 c.1797+1G>A](/variant/ano10-c-1797-plus-1g-a), [ANO10 c.472+1G>T](/variant/ano10-c-472-plus-1g-t), [ANO10 c.473-2A>G](/variant/ano10-c-473-minus-2a-g), [ANO10 c.473-2A>T](/variant/ano10-c-473-minus-2a-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 3369621). 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.*