ClinGen expert panel — Mitochondrial Diseases VCEP
Benign for ethylmalonic encephalopathy. Applied ACMG criteria (verbatim):
BS2 BP7 BA1
Curation rationale (ClinGen, verbatim)
The allele frequency of the c.6G>A variant in the ETHE1 gene is reported as >16% in gnomAD, including >2,000 homozygotes, which is high enough to be classified as benign based on thresholds defined by the ClinGen ETHE1 Variant Curation Expert Panel (>0.1% in gnomAD- BA1 and BS2). In silico splicing predictors (Splice AI) do not predict a deleterious effect (BP7). In summary, this variant meets criteria to be classified as benign for ETHE1-related ethylmalonic encephalopathy. ETHE1-specific ACMG/AMP criteria applied: (BA1, BS2, BP7).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
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 -1.9 | GERP -2.3 |
| Overall | ||
| CADD | 5.062 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Finnishnot grpmax-eligible | 21.5% | 5 |
| European (non-Finnish)grpmax | 19.6% | 5 |
| Remaining individualsnot grpmax-eligible | 17.2% | 6 |
| African / African-American | 17% | 6 |
| South Asian | 15.1% | 7 |
| Ashkenazi Jewishnot grpmax-eligible | 15.1% | 7 |
| East Asian | 14.7% | 7 |
| Middle Eastern | 11.9% | 8 |
| Amishnot grpmax-eligible | 11.1% | 9 |
| Admixed American | 8.97% | 11 |
Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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
- ETHE1
- Protein
- p.Ala2=
- Coding
- c.6G>A
- MANE Select
- NM_014297
- dbSNP
- rs3810381
- Type
- single nucleotide variant
- Location
- chr19:43527172 (GRCh38)
- Gene constraint
- LOEUF 0.97 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 93.05 · 1 PDB
Disease context
ethylmalonic encephalopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Ethylmalonic encephalopathy (Orphanet):
- Inheritance
- Autosomal recessive
- Onset
- Infancy, Neonatal
Similar variants
- ETHE1 c.505+1G>A Pathogenic ★★★ same condition
- ETHE1 c.505+1G>T Pathogenic ★★★ same condition
- ETHE1 p.Arg163Gln Pathogenic ★★★ same condition
- ETHE1 p.Arg163Trp Pathogenic ★★★ same condition
- ETHE1 p.Ala254Val Uncertain significance ★★★ ⚠ same condition
- ETHE1 p.Arg124Leu Uncertain significance ★★★ ⚠ same condition
- ETHE1 p.Lys66Arg Uncertain significance ★★★ ⚠ same condition
- ETHE1 p.Val143Ile Uncertain significance ★★★ ⚠ same condition
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/ethe1-p-ala2 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown