# NM_213599.3(ANO5):c.729T>C (p.Ser243=)

https://sugi.bio/variant/ano5-p-ser243

## Summary

**ANO5 p.Ser243= (c.729T>C)** is classified **Likely benign** in ANO5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-18). Very rare (popmax 0.00333%, amr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2L.

**At a glance:** Likely benign · review: Single submitter · rsID rs776237436 · 1 submitter · 2 linked conditions · very rare (popmax 0.00333%, amr)

## 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.Ser243= |
| Coding change (HGVS c.) | c.729T>C |
| MANE Select transcript | [NM_213599](https://www.ncbi.nlm.nih.gov/nuccore/NM_213599) |
| dbSNP | [rs776237436](https://www.ncbi.nlm.nih.gov/snp/rs776237436/) |
| Variant type | single nucleotide variant |
| Location | chr11:22236243-22236243 (GRCh38) |
| ClinVar | [VCV707088](https://www.ncbi.nlm.nih.gov/clinvar/variation/707088/) |

**All HGVS expressions:** `LRG_868:g.48068T>C`, `LRG_868t1:c.729T>C`, `NC_000011.10:g.22236243T>C`, `NC_000011.9:g.22257789T>C`, `NG_015844.1:g.48068T>C`, `NM_001142649.2:c.726T>C`, `NM_213599.3:c.729T>C`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.27) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.836, GERP -5.47 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.897**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.27**. Largest is donor gain, 33 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00333%** (amr) · FAF95 0.000553% · FAF99 0.000207% · 2/59,974 in the highest group · 4/1,613,134 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 29,987 |
| European (non-Finnish) | 0.00017% | 589,668 |

*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 2023-09-18.

**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 | 2023-09-18 |

## 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, Limb-girdle muscular dystrophy, type 2L, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 12, Limb-Girdle Muscular Dystrophy R12 Anoctamin-5-Related (LGMD-R12), OSTEOGENESIS IMPERFECTA WITH UNUSUAL SKELETAL LESIONS, GNATHODIAPHYSEAL SCLEROSIS.

## Similar variants {#similar}

Related ANO5 variant pages (same residue, condition, or type): [ANO5 p.Ser243Tyr](/variant/ano5-p-ser243tyr), [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), [ANO5 p.Arg58Trp](/variant/ano5-p-arg58trp), [ANO5 p.Arg758Cys](/variant/ano5-p-arg758cys).

### 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 707088). 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.*