ACO2 p.Pro539=
c.1617A>G · rs554206446 · VCV729352
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
rare (popmax 0.156%, 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 -13 | GERP -3.7 |
| Overall | ||
| CADD | 0.764 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.156%
South Asian · 142/91,074 alleles
Filtering AF
0.135%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.127%
Overall
0.00929%
150/1,613,982 alleles · rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.156% | 641 |
| Remaining individualsnot grpmax-eligible | 0.008% | 12,499 |
| European (non-Finnish) | 0.000254% | 393,306 |
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
- ACO2
- Protein
- p.Pro539=
- Coding
- c.1617A>G
- MANE Select
- NM_001098
- dbSNP
- rs554206446
- Type
- single nucleotide variant
- Location
- chr22:41525204 (GRCh38)
- Gene constraint
- LOEUF 0.489 · pLI 0.98 (gnomAD)
- Structure
- AlphaFold pLDDT 95.44
- Residue 539
- the 'disordered' region
Similar variants
- ACO2 p.Pro539Arg Uncertain significance ★ ⚠ same residue
- ACO2 p.Arg378Ter Pathogenic/Likely pathogenic ★★ same type
- ACO2 p.Arg58Ter Pathogenic/Likely pathogenic ★★ same type
- ACO2 p.Arg84Ter Pathogenic ★★ same type
- ACO2 p.Glu464Ter Pathogenic/Likely pathogenic ★★ same type
- ACO2 p.Gly503Ter Pathogenic ★★ same type
- ACO2 c.1605+5G>C Uncertain significance ★★ same type
- ACO2 c.2208+5G>C Uncertain significance ★★ 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/aco2-p-pro539 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown