CLCN4 p.Pro709=
c.2127G>A · rs376156924 · VCV1166236
Benign
Single submitter
Classification
Benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0297%, afr)
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 -3.9 | GERP -4.1 |
| Overall | ||
| CADD | 1.787 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0297%
African / African-American · 17/57,237 alleles
Filtering AF
0.0189%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0155%
Overall
0.0019%
23/1,210,270 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0297% | 3,367 |
| Admixed American | 0.00655% | 15,266 |
| Remaining individualsnot grpmax-eligible | 0.0021% | 47,595 |
| European (non-Finnish) | 0.000223% | 447,632 |
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.Pro709=
- Coding
- c.2127G>A
- MANE Select
- NM_001830
- dbSNP
- rs376156924
- Type
- single nucleotide variant
- Location
- chrX:10220812 (GRCh38)
- Structure
- AlphaFold pLDDT 84.66
- Residue 709
- the cbs 2 domain
Similar variants
- CLCN4 p.Pro709Leu 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-pro709 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown