ACO1 p.Glu421=
c.1263A>G · VCV4683381
Benign
Single submitter
Classification
Benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Common
common (popmax 51.4%, eas) — too common for a highly-penetrant pathogenic allele
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 0.037 | GERP -2.4, phastCons 0.043 |
| Overall | ||
| CADD | 5.323 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
51.4%
East Asian · 23,043/44,846 alleles
Filtering AF
50.8%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 50.6%
Overall
35%
563,795/1,612,936 alleles · common
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 51.4% | 2 |
| Amishnot grpmax-eligible | 44.8% | 2 |
| European (non-Finnish) | 35.7% | 3 |
| Remaining individualsnot grpmax-eligible | 34.2% | 3 |
| Admixed American | 33.7% | 3 |
| Ashkenazi Jewishnot grpmax-eligible | 32.3% | 3 |
| Finnishnot grpmax-eligible | 30.3% | 3 |
| South Asian | 29.2% | 3 |
| Middle Eastern | 27.5% | 4 |
| African / African-American | 26.9% | 4 |
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
- ACO1
- Protein
- p.Glu421=
- Coding
- c.1263A>G
- MANE Select
- NM_002197
- Type
- single nucleotide variant
- Location
- chr9:32425912 (GRCh38)
- Gene constraint
- LOEUF 0.839 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 94.75 · 2 PDB
- Residue 421
- a β-strand
Similar variants
- ACO1 p.Glu421Lys Uncertain significance ★ ⚠ same residue
- ACO1 p.Ala665Val Uncertain significance ★★ ⚠ same type
- ACO1 p.Arg885His Uncertain significance ★★ same type
- ACO1 p.Gly831Arg Uncertain significance ★★ ⚠ same type
- ACO1 p.Ala794= Benign ★★ same type
- ACO1 p.Asp569= Benign ★★ same type
- ACO1 p.His252= Benign ★★ same type
- ACO1 p.Pro443= Benign/Likely benign ★★ 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/aco1-p-glu421 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown