EARS2 p.Val292Ile
c.874G>A · rs199575087 · VCV318551
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0734 | likely benign |
|---|---|---|
| REVEL | 0.083 | moderately benign-leaning |
| SaProt | LLR -6.61 | tolerated |
| ⇒ AlphaMissense, REVEL and SaProt all call this tolerated. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 2.9 | GERP 0.62, phastCons 1 |
| Regional constraint | o/e 0.94 | unconstrained · MANE · 11 kb · p 0.22 · regional, not allelic |
| Overall | ||
| CADD | 15.26 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Ashkenazi Jewishnot grpmax-eligible | 0.352% | 284 |
| Remaining individualsnot grpmax-eligible | 0.0433% | 2,310 |
| Middle Easterngrpmax | 0.0344% | 2,910 |
| African / African-American | 0.0293% | 3,410 |
| Admixed American | 0.0217% | 4,607 |
| European (non-Finnish) | 0.0126% | 7,909 |
| South Asian | 0.0011% | 90,888 |
Ashkenazi Jewish 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
- EARS2
- Protein
- p.Val292Ile
- Coding
- c.874G>A
- MANE Select
- NM_001083614
- dbSNP
- rs199575087
- Type
- single nucleotide variant
- Location
- chr16:23534972 (GRCh38)
- Gene constraint
- LOEUF 1.138 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 89.84
Disease context
leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: mitochondrial disease
For Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (Orphanet):
- Inheritance
- No data available
- Onset
- Infancy, Neonatal
Similar variants
- EARS2 p.Val292Ala Uncertain significance ★ ⚠ same residue
- EARS2 p.Val292Phe Uncertain significance ★ ⚠ same residue
- EARS2 p.Val292Leu Uncertain significance ⚠ same residue
- EARS2 p.Arg107His Pathogenic/Likely pathogenic ★★ ⚠ same condition
- EARS2 p.Arg108Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
- EARS2 p.Cys167Tyr Pathogenic/Likely pathogenic ★★ same condition
- EARS2 p.Met1Val Pathogenic/Likely pathogenic ★★ same condition
- EARS2 p.Ser143Ter Pathogenic ★★ 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/ears2-p-val292ile (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown