CLCN4 p.Pro684=
c.2052G>A · rs777620754 · VCV1170788
Benign
Single submitter
Classification
Benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00352%, sas)
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 -3.4 | GERP -4.4 |
| Overall | ||
| CADD | 0.525 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00352%
South Asian · 2/56,799 alleles
Filtering AF
0.000584%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000278%
Overall
0.00116%
14/1,209,711 alleles · very rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.00352% | 28,399 |
| African / African-American | 0.0035% | 28,573 |
| Admixed American | 0.00219% | 45,742 |
| Remaining individualsnot grpmax-eligible | 0.0021% | 47,609 |
| European (non-Finnish) | 0.000894% | 111,879 |
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
- CLCN4
- Protein
- p.Pro684=
- Coding
- c.2052G>A
- MANE Select
- NM_001830
- dbSNP
- rs777620754
- Type
- single nucleotide variant
- Location
- chrX:10220737 (GRCh38)
- Structure
- AlphaFold pLDDT 84.66
- Residue 684
- the 'required for localization in the endoplasmic reticulum' region
Similar variants
- CLCN4 p.Pro684Leu Uncertain significance ★★ ⚠ same residue
- CLCN4 c.844-1G>A Pathogenic/Likely pathogenic ★★ same type
- CLCN4 p.Ala555Val Pathogenic ★★ ⚠ same type
- CLCN4 p.Arg718Trp Pathogenic ★★ same type
- CLCN4 p.Asp89Asn Pathogenic/Likely pathogenic ★★ ⚠ same type
- CLCN4 p.Gly467Ser Likely pathogenic ★★ same type
- CLCN4 p.Gly544Arg Pathogenic ★★ same type
- CLCN4 p.Gly731Arg 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/clcn4-p-pro684 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown