ESCO2 p.Pro228=
c.684G>A · rs146523589 · VCV799167
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00339%, nfe)
Conditions
1
Roberts-SC phocomelia syndrome
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 -1.5 | GERP -2.9 |
| Overall | ||
| CADD | 4.794 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00339%
European (non-Finnish) · 40/1,179,710 alleles
Filtering AF
0.00255%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00225%
Overall
0.00298%
48/1,612,856 alleles · very rare
exomes 45/1,460,758 · genomes 3/152,098 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.00339% | 29,493 |
| Admixed American | 0.00335% | 29,872 |
| South Asian | 0.0033% | 30,270 |
| African / African-American | 0.00268% | 37,368 |
| Finnishnot grpmax-eligible | 0.00156% | 64,000 |
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
- ESCO2
- Protein
- p.Pro228=
- Coding
- c.684G>A
- MANE Select
- NM_001017420
- dbSNP
- rs146523589
- Type
- single nucleotide variant
- Location
- chr8:27776992 (GRCh38)
- Gene constraint
- LOEUF 1.013 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 58.81
- Residue 228
- the 'disordered' region
Similar variants
- ESCO2 c.1013+1G>A Likely pathogenic ★★ same condition
- ESCO2 c.1131+1G>A Pathogenic ★★ same condition
- ESCO2 c.1131+1G>T Pathogenic ★★ same condition
- ESCO2 c.1132-7A>G Pathogenic/Likely pathogenic ★★ same condition
- ESCO2 c.1353+1G>T Likely pathogenic ★★ same condition
- ESCO2 p.Arg169Ter Pathogenic ★★ same condition
- ESCO2 p.Arg552Ter Pathogenic/Likely pathogenic ★★ same condition
- ESCO2 p.Gln409Ter Pathogenic/Likely 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/esco2-p-pro228 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown