EARS2 p.Pro21=
c.63C>A · rs113410455 · VCV2713807
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0389%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.019 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · G>C here scores Δ0.42 · evaluated, not missing |
| Constraint at this position | ||
| Conservation | phyloP -1.4 | GERP -3.7 |
| Overall | ||
| CADD | 0.645 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0389%
African / African-American · 28/72,062 alleles
Filtering AF
0.0276%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0238%
Overall
0.00343%
52/1,516,902 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0389% | 2,574 |
| Middle Eastern | 0.0355% | 2,814 |
| Admixed American | 0.0213% | 4,702 |
| Remaining individualsnot grpmax-eligible | 0.00684% | 14,628 |
| European (non-Finnish) | 0.000787% | 127,137 |
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.Pro21=
- Coding
- c.63C>A
- MANE Select
- NM_001083614
- dbSNP
- rs113410455
- Type
- single nucleotide variant
- Location
- chr16:23557281 (GRCh38)
- Gene constraint
- LOEUF 1.138 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 89.84
Similar variants
- EARS2 p.Pro21Thr Uncertain significance ★ ⚠ same residue
- EARS2 p.Arg107His Pathogenic/Likely pathogenic ★★ ⚠ same type
- EARS2 p.Arg108Trp Pathogenic/Likely pathogenic ★★ ⚠ same type
- EARS2 p.Cys167Tyr Pathogenic/Likely pathogenic ★★ same type
- EARS2 p.Gly317Cys Pathogenic ★★ same type
- EARS2 p.Met1Val Pathogenic/Likely pathogenic ★★ same type
- EARS2 p.Ser143Ter Pathogenic ★★ same type
- EARS2 p.Ala263Thr 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/ears2-p-pro21 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown