ESPN p.Pro433fs
c.1293_1296del · VCV4930797
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 7 of 13 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 0.81 | GERP 0.28, phastCons 0.21 |
| Overall | ||
| CADD | 26.7 | PHRED · no single calibrated threshold — expert panels disagree |
| Region caveats | ||
| Repeat context | seg dup | · reads may not map uniquely · confidence, not pathogenicity |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Amishnot grpmax-eligible | 1.64% | 61 |
| African / African-Americangrpmax | 0.723% | 138 |
| Admixed American | 0.475% | 210 |
| East Asian | 0.334% | 300 |
| Ashkenazi Jewishnot grpmax-eligible | 0.278% | 360 |
| Finnishnot grpmax-eligible | 0.22% | 455 |
| Remaining individualsnot grpmax-eligible | 0.166% | 603 |
| European (non-Finnish) | 0.166% | 604 |
| South Asian | 0.134% | 745 |
| Middle Eastern | 0.0948% | 1,055 |
Amish 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
- ESPN
- Protein
- p.Pro433fs
- Coding
- c.1293_1296del
- MANE Select
- NM_031475
- Type
- Deletion
- Location
- chr1:6445764 (GRCh38)
- Gene constraint
- LOEUF 1.307 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 68.76
- Residue 433
- the 'disordered' region
Similar variants
- ESPN p.Pro433Ser Uncertain significance ★ ⚠ same residue
- ESPN p.Pro433= Likely benign ★ same residue
- ESPN p.Arg632_Ser633delinsPro Uncertain significance ★★ same type
- ESPN p.Leu366del Uncertain significance ★★ same type
- ESPN c.1464+19del Benign/Likely benign ★★ same type
- ESPN p.Pro602_Pro605del Benign/Likely benign ★★ same type
- ESPN c.487_488+2del Likely pathogenic ★ same type
- ESPN p.Arg550fs Pathogenic ★ 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/espn-p-pro433fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown