# NM_213599.3(ANO5):c.546C>T (p.Pro182=)

https://sugi.bio/variant/ano5-p-pro182

## Summary

**ANO5 p.Pro182= (c.546C>T)** is classified **Likely benign** in ANO5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-08). Ultra-rare (popmax 0.022%, sas); Associated with autosomal recessive limb-girdle muscular dystrophy type 2L.

**At a glance:** Likely benign · review: Single submitter · rsID rs753909670 · 1 submitter · 2 linked conditions · ultra-rare (popmax 0.022%, sas)

## For patients & families {#patients}

This is a change in the ANO5 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to autosomal recessive limb-girdle muscular dystrophy type 2L.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ANO5 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Anoctamin-5-related limb-girdle muscular dystrophy R12** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Myalgia — Very frequent (99-80%)
- Limb-girdle muscular dystrophy — Very frequent (99-80%)
- Proximal muscle weakness in lower limbs — Very frequent (99-80%)
- Distal lower limb muscle weakness — Very frequent (99-80%)
- Abnormality of the calf musculature — Frequent (79-30%)
- Genu recurvatum — Frequent (79-30%)
- Elevated circulating creatine kinase concentration — Frequent (79-30%)
- EMG: neuropathic changes — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012536/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ANO5](https://sugi.bio/atlas/gene/ANO5/) |
| Protein change (HGVS p.) | p.Pro182= |
| Coding change (HGVS c.) | c.546C>T |
| MANE Select transcript | [NM_213599](https://www.ncbi.nlm.nih.gov/nuccore/NM_213599) |
| dbSNP | [rs753909670](https://www.ncbi.nlm.nih.gov/snp/rs753909670/) |
| Variant type | single nucleotide variant |
| Location | chr11:22227484-22227484 (GRCh38) |
| ClinVar | [VCV1910941](https://www.ncbi.nlm.nih.gov/clinvar/variation/1910941/) |

**All HGVS expressions:** `LRG_868:g.39309C>T`, `LRG_868t1:c.546C>T`, `NC_000011.10:g.22227484C>T`, `NC_000011.9:g.22249030C>T`, `NG_015844.1:g.39309C>T`, `NM_001142649.2:c.543C>T`, `NM_001410963.1:c.504C>T`, `NM_001410964.1:c.501C>T`, `NM_213599.3:c.546C>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 -0.267, GERP -4.9 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.537**. 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 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 **0.022%** (sas) · FAF95 0.0145% · FAF99 0.0121% · 20/91,076 in the highest group · 22/1,613,446 alleles overall — ultra-rare (popmax 0.022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.022% | 4,554 |
| Admixed American | 0.00334% | 29,938 |

*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}

**ANO5** population constraint: LOEUF 1.034, pLI 2.1745e-26, missense-Z 0.71114. *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 limb-girdle muscular dystrophy** — Definitive (AR)
- **gnathodiaphyseal dysplasia** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.22, 39% of residues very-high.

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

*Describes the biological roles of ANO5 (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:** ANO5's established molecular role includes intracellularly calcium-gated chloride channel activity. In Reactome, ANO5 is annotated in disease pathway(s) including **Induction of Cell-Cell Fusion**.

**Disease mechanism (Reactome):** ANO5 loss or alteration is curated in [Induction of Cell-Cell Fusion](https://reactome.org/content/detail/R-HSA-9733458).

### Pathways affected {#pathways}

ANO5 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Induction of Cell-Cell Fusion](https://reactome.org/content/detail/R-HSA-9733458) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

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

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

**Biological process:** plasma membrane repair, chloride transmembrane transport.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-08.

**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 | 2024-04-08 |

## Associated conditions {#conditions}

[autosomal recessive limb-girdle muscular dystrophy type 2L](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2l/), [gnathodiaphyseal dysplasia](https://sugi.bio/atlas/disease/gnathodiaphyseal-dysplasia/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy type 2L, Gnathodiaphyseal dysplasia, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 12, Limb-Girdle Muscular Dystrophy R12 Anoctamin-5-Related (LGMD-R12), Limb-girdle muscular dystrophy, type 2L, GNATHODIAPHYSEAL SCLEROSIS, OSTEOGENESIS IMPERFECTA WITH UNUSUAL SKELETAL LESIONS.

## Similar variants {#similar}

Related ANO5 variant pages (same residue, condition, or type): [ANO5 p.Pro182Leu](/variant/ano5-p-pro182leu), [ANO5 p.Pro182Ala](/variant/ano5-p-pro182ala), [ANO5 p.Pro182_Tyr186del](/variant/ano5-p-pro182-tyr186del), [ANO5 c.1898+1G>A](/variant/ano5-c-1898-plus-1g-a), [ANO5 c.41-1G>A](/variant/ano5-c-41-minus-1g-a), [ANO5 p.Ala432Gly](/variant/ano5-p-ala432gly), [ANO5 p.Arg484Cys](/variant/ano5-p-arg484cys), [ANO5 p.Arg50Ter](/variant/ano5-p-arg50ter).

### 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 1910941). 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.*