# NM_031418.4(ANO3):c.609C>T (p.Pro203=)

https://sugi.bio/variant/ano3-p-pro203

## Summary

**ANO3 p.Pro203= (c.609C>T)** is classified **Likely benign** in ANO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-03). Very rare (popmax 0.00134%, afr); Associated with dystonic disorder.

**At a glance:** Likely benign · review: Single submitter · rsID rs778253031 · 1 submitter · 1 linked condition · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the ANO3 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to dystonic disorder.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 170 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027640/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ANO3](https://sugi.bio/atlas/gene/ANO3/) |
| Protein change (HGVS p.) | p.Pro203= |
| Coding change (HGVS c.) | c.609C>T |
| MANE Select transcript | [NM_031418](https://www.ncbi.nlm.nih.gov/nuccore/NM_031418) |
| dbSNP | [rs778253031](https://www.ncbi.nlm.nih.gov/snp/rs778253031/) |
| Variant type | single nucleotide variant |
| Location | chr11:26516844-26516844 (GRCh38) |
| ClinVar | [VCV2418099](https://www.ncbi.nlm.nih.gov/clinvar/variation/2418099/) |

**All HGVS expressions:** `NC_000011.10:g.26516844C>T`, `NC_000011.9:g.26538391C>T`, `NG_042856.1:g.332722C>T`, `NM_001313726.2:c.792C>T`, `NM_001313727.2:c.171C>T`, `NM_031418.4:c.609C>T`

## 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 -1.326, GERP -3.78 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.615**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.20 acceptor 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 (gnomAD v4.1): grpmax **0.00134%** (afr) · FAF95 0.000616% · FAF99 0.000475% · 1/74,860 in the highest group · 16/1,458,676 alleles overall — very rare (popmax 0.00134%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,171 |
| African / African-American (grpmax) | 0.00134% | 74,860 |
| European (non-Finnish) | 0.0011% | 90,590 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**ANO3** population constraint: LOEUF 0.911, pLI 5.0884e-18, missense-Z 2.8578. *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 76.30, 34% of residues very-high.

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

*Describes the biological roles of ANO3 (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:** ANO3 participates in disease-associated pathways. In Reactome, ANO3 is annotated in disease pathway(s) including **Induction of Cell-Cell Fusion**.

**Disease mechanism (Reactome):** ANO3 loss or alteration is curated in [Induction of Cell-Cell Fusion](https://reactome.org/content/detail/R-HSA-9733458).

### Pathways affected {#pathways}

ANO3 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 |

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-03.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-03 |

## Associated conditions {#conditions}

[dystonic disorder](https://sugi.bio/atlas/disease/dystonic-disorder/).

**Reported phenotype names (ClinVar):** Dystonic disorder, Dystonia.

## Similar variants {#similar}

Related ANO3 variant pages (same residue, condition, or type): [ANO3 p.Pro203Ala](/variant/ano3-p-pro203ala), [MUC15 p.Thr203Ala](/variant/muc15-p-thr203ala), [ANO3 p.Ala657Thr](/variant/ano3-p-ala657thr), [ANO3 p.Asn648Ser](/variant/ano3-p-asn648ser), [ANO3 p.Glu510Lys](/variant/ano3-p-glu510lys), [ANO3 c.1836+4A>C](/variant/ano3-c-1836-plus-4a-c), [ANO3 c.2141+1G>A](/variant/ano3-c-2141-plus-1g-a), [ANO3 c.2276-6T>C](/variant/ano3-c-2276-minus-6t-c).

### 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 2418099). 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.*