ESPN p.Thr649=
c.1947G>A · rs377497281 · VCV227359
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00424%, nfe)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.94 | acceptor gain · deltas |
|---|---|---|
| Pangolin | Δ0.44 | gain · loss 0.05 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP -0.73 | GERP -2.8, phastCons 0.001 |
| Overall | ||
| CADD | 23.0 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00424%
European (non-Finnish) · 50/1,179,934 alleles
Filtering AF
0.00326%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00294%
Overall
0.0036%
58/1,613,066 alleles · very rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.00424% | 23,599 |
| Admixed American | 0.00334% | 29,976 |
| South Asian | 0.0033% | 30,330 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,232 |
| East Asian | 0.00223% | 44,882 |
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.Thr649=
- Coding
- c.1947G>A
- MANE Select
- NM_031475
- dbSNP
- rs377497281
- Type
- single nucleotide variant
- Location
- chr1:6451634 (GRCh38)
- Gene constraint
- LOEUF 1.307 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 68.76
- Residue 649
- the 'disordered' region
Similar variants
- ESPN p.Thr649Met Uncertain significance ★★ ⚠ same residue
- ESPN p.Thr649Lys Uncertain significance ★ ⚠ same residue
- ESPN c.1464+1G>A Likely pathogenic ★★ same type
- ESPN p.Ala139Thr Uncertain significance ★★ ⚠ same type
- ESPN p.Ala23Thr Uncertain significance ★★ ⚠ same type
- ESPN p.Ala484Thr Uncertain significance ★★ ⚠ same type
- ESPN p.Ala591Val Uncertain significance ★★ ⚠ same type
- ESPN p.Ala610Pro 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/espn-p-thr649 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown