CLCN2 p.Ala760=
c.2280G>A · VCV4083967
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0171%, mid)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -11 | GERP -3.1 |
| Overall | ||
| CADD | 0.084 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0171%
Middle Eastern · 1/5,846 alleles
Filtering AF
0.0106%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00997%
Overall
0.0101%
163/1,613,536 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0171% | 5,846 |
| European (non-Finnish) | 0.0123% | 8,138 |
| Remaining individualsnot grpmax-eligible | 0.00961% | 10,409 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00676% | 14,802 |
| Admixed American | 0.005% | 19,995 |
| South Asian | 0.00329% | 30,351 |
| African / African-American | 0.00267% | 37,442 |
| East Asian | 0.00223% | 44,884 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- CLCN2
- Protein
- p.Ala760=
- Coding
- c.2280G>A
- MANE Select
- NM_004366
- Type
- single nucleotide variant
- Location
- chr3:184352323 (GRCh38)
- Gene constraint
- LOEUF 0.786 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 72.82 · 8 PDB
- Residue 760
- a UniProt-annotated variant site (in lkpat; decreased voltage-gated chloride channel activity; does not affect protein expression; does not affect localization at the cell membrane)
Similar variants
- CLCN2 p.Ala760Val Uncertain significance ★★ ⚠ same residue
- CLCN2 p.Ala760Ser Uncertain significance ★ ⚠ same residue
- CLCN2 c.898+1G>A Likely pathogenic ★★ same type
- CLCN2 p.Arg172Gln Pathogenic ★★ same type
- CLCN2 p.Arg610Ter Pathogenic/Likely pathogenic ★★ same type
- CLCN2 p.Glu619Ter Pathogenic/Likely pathogenic ★★ same type
- CLCN2 p.Gly24Asp Pathogenic/Likely pathogenic ★★ ⚠ same type
- CLCN2 p.Trp570Ter Pathogenic/Likely pathogenic ★★ same type
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/clcn2-p-ala760 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown