# NM_001025356.3(ANO6):c.1920T>G (p.Ser640=)

https://sugi.bio/variant/ano6-p-ser640

## Summary

**ANO6 p.Ser640= (c.1920T>G)** is classified **Likely benign** in ANO6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-08). Rare (popmax 0.193%, sas).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs530970448 · 2 submitters · rare (popmax 0.193%, sas)

## For patients & families {#patients}

This is a change in the ANO6 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters.

*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 | [ANO6](https://sugi.bio/atlas/gene/ANO6/) |
| Protein change (HGVS p.) | p.Ser640= |
| Coding change (HGVS c.) | c.1920T>G |
| MANE Select transcript | [NM_001025356](https://www.ncbi.nlm.nih.gov/nuccore/NM_001025356) |
| dbSNP | [rs530970448](https://www.ncbi.nlm.nih.gov/snp/rs530970448/) |
| Variant type | single nucleotide variant |
| Location | chr12:45409396-45409396 (GRCh38) |
| ClinVar | [VCV257144](https://www.ncbi.nlm.nih.gov/clinvar/variation/257144/) |

**All HGVS expressions:** `LRG_877:g.198410T>G`, `LRG_877t1:c.1920T>G`, `LRG_877t2:c.1866T>G`, `LRG_877t3:c.1920T>G`, `LRG_877t4:c.1983T>G`, `NC_000012.11:g.45803179T>G`, `NC_000012.12:g.45409396T>G`, `NG_028220.1:g.198410T>G`, `NM_001025356.3:c.1920T>G`, `NM_001142678.2:c.1866T>G`, `NM_001142679.2:c.1920T>G`, `NM_001204803.2:c.1983T>G`

## 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 -9.869, GERP -4.77 — fast-evolving / accelerated position
- CADD: **PHRED 0.165**. 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 **0.193%** (sas) · FAF95 0.17% · FAF99 0.161% · 176/91,082 in the highest group · 185/1,614,086 alleles overall — rare (popmax 0.193%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.193% | 518 |
| Remaining individuals (not grpmax-eligible) | 0.0144% | 6,945 |

*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}

**ANO6** population constraint: LOEUF 1.02, pLI 2.4628e-30, missense-Z 2.4132. *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):

- **Scott syndrome** — Moderate (AR)

## Protein context {#protein}

Residue **640** lies in a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 82.00, 38% of residues very-high.

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

*Describes the biological roles of ANO6 (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:** ANO6's established molecular role includes calcium-activated cation channel activity. In Reactome, ANO6 is annotated in disease pathway(s) including **Defective ANO6 does not expose PS, PE on the platelet membrane**, **Induction of Cell-Cell Fusion**.

**Disease mechanism (Reactome):** ANO6 loss or alteration is curated in [Defective ANO6 does not expose PS, PE on the platelet membrane](https://reactome.org/content/detail/R-HSA-9853846), [Induction of Cell-Cell Fusion](https://reactome.org/content/detail/R-HSA-9733458).

### Pathways affected {#pathways}

ANO6 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective ANO6 does not expose PS, PE on the platelet membrane](https://reactome.org/content/detail/R-HSA-9853846) | curated |
| ⚕ [Induction of Cell-Cell Fusion](https://reactome.org/content/detail/R-HSA-9733458) | curated |
| [Amplification and propagation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769743) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | 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:** calcium-activated cation channel activity, intracellularly calcium-gated chloride channel activity, voltage-gated chloride channel activity, phospholipid scramblase activity.

**Biological process:** activation of blood coagulation via clotting cascade, plasma membrane phospholipid scrambling, positive regulation of bone mineralization, bleb assembly, positive regulation of monoatomic ion transmembrane transport, purinergic nucleotide receptor signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-08.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-08 |

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

## Similar variants {#similar}

Related ANO6 variant pages (same residue, condition, or type): [ANO6 c.1387-1G>T](/variant/ano6-c-1387-minus-1g-t), [ANO6 p.Arg253Cys](/variant/ano6-p-arg253cys), [ANO6 p.Arg253His](/variant/ano6-p-arg253his), [ANO6 p.Arg276Gln](/variant/ano6-p-arg276gln), [ANO6 p.Arg399Cys](/variant/ano6-p-arg399cys), [ANO6 p.Arg635Gln](/variant/ano6-p-arg635gln), [ANO6 p.Arg648Leu](/variant/ano6-p-arg648leu), [ANO6 p.Arg862Cys](/variant/ano6-p-arg862cys).

### 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 257144). 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.*